History of RNA biology
Encyclopedia
Numerous key discoveries in biology
have emerged from studies of RNA
(ribonucleic acid), including seminal work in the fields of biochemistry
, genetics
, microbiology
, molecular biology
, molecular evolution
and structural biology
. As of 2010, 30 scientists have been awarded Nobel Prize
s for experimental work that includes studies of RNA. Specific discoveries of high biological significance are discussed in this article.
For related information, see the articles on History of Molecular Biology
and History of Genetics
. For background information, see the articles on RNA
and nucleic acid
.
nucleic acid" and DNA was "pancreas
nucleic acid". Using diagnostic chemical tests, carbohydrate
chemists showed that the two nucleic acids contained different sugars, whereupon the common name for RNA became "ribose nucleic acid". Other early biochemical studies showed that RNA was readily broken down at high pH
, while DNA was stable (although denatured) in alkali
. Nucleoside composition analysis showed first that RNA contained similar nucleobase
s to DNA, with uracil
instead of thymine
, and that RNA contained a number of minor nucleobase components, e.g. small amounts of pseudouridine
and dimethylguanine.
's description of his "Central Dogma of Molecular Biology", which asserted that DNA led to the formation of RNA, which in turn led to the synthesis of protein
s. During the early 1960s, sophisticated genetic analysis of mutations in the lac operon
of E. coli
and in the rII locus of bacteriophage T4
were instrumental in defining the nature of both messenger RNA
and the genetic code
. The short-lived nature of bacterial RNAs, together with the highly complex nature of the cellular mRNA population, made the biochemical isolation of mRNA very challenging. This problem was overcome in the 1960s by the use of reticulocyte
s in vertebrates, which produce large quantities of mRNA that are highly enriched in RNA encoding alpha- and beta-globin (the two major protein chains of hemoglobin
).
s were found to be associated with "microsomes" (later redefined as ribosomes) very rapidly after administration, and before they became widely incorporated into cellular proteins. Ribosomes were first visualized using electron microscopy, and their ribonucleoprotein components were identified by biophysical methods, chiefly sedimentation analysis within ultracentrifuges capable of generating very high accelerations (equivalent to hundreds of thousands times gravity). Polysomes (multiple ribosomes moving along a single mRNA molecule) were identified in the early 1960s, and their study led to an understanding of how ribosomes proceed to read the mRNA in a 5' to 3' direction, processively generating proteins as they do so.
s responsible for linking tRNAs with the correct amino acids, and (iii) that tRNA anticodon sequences form a specific decoding interaction with mRNA codons.
consists of the translation of particular nucleotide sequences in mRNA to specific amino acid sequences in proteins (polypeptides). The ability to work out out the genetic code emerged from the convergence of three different areas of study--(i) new methods to generate synthetic RNA molecules of defined composition to serve as artificial mRNAs, (ii) development of in vitro translation systems that could used to translate the synthetic mRNAs into protein, and (iii) experimental and theoretical genetic work which established that the code was written in three letter "words" (codons). Today, our understanding of the genetic code permits the prediction of the amino sequence of the protein products of the tens of thousands of genes whose sequences are being determined in genome studies
.
from the bacterium Escherichia coli
enabled the understanding of the mechanisms through which RNA polymerase initiates and terminates transcription
, and how those processes are regulated to regulate gene expression
(i.e. turn genes on and off). Following the isolation of E. coli RNA polymerase, the three RNA polymerases of the eukaryotic nucleus were identified, as well as those associated with viruses and organelles. Studies of transcription also led to the identification of many protein factors that influence transcription, including repressors, activators and enhancers. The availability of purified preparations of RNA polymerase permitted investigators to develop a wide range of novel methods for studying RNA in the test tube, and led directly to many of the subsequent key discoveries in RNA biology.
MS2 was determined by a large team of researchers over several years, and was reported in a series of scientific papers. These results enabled the analysis of the first complete genome, albeit an extremely tiny one by modern standards. Several surprising features were identified, including genes that partially overlap one another and the first clues that different organisms might have slightly different codon usage patterns.
) that is essential for this process. Some retroviruses can cause diseases, including several that are associated with cancer, and HIV-1 which causes AIDS. Reverse transcriptase has been widely used as an experimental tool for the analysis of RNA molecules in the laboratory, in particular the conversion of RNA molecules into DNA prior to molecular cloning
and/or polymerase chain reaction
(PCR).
sequences from a large number of organisms demonstrated that all extant forms of life on Earth share common structural and sequence features of the ribosomal RNA, reflecting a common ancestry. Mapping the similarities and differences among rRNA molecules from different sources provides clear and quantitative information about the phylogenetic (i.e. evolutionary) relationships among organisms. Analysis of rRNA molecules led to the identification of a third major kingdom of organisms, the archaea
, in addition to the prokaryotes and eukaryotes.
molecules (snRNAs) were identified in the eukaryotic nucleus
using immunological studies with autoimmune antibodies, which bind to small nuclear ribonucleoprotein
complexes (snRNPs; complexes of the snRNA and protein). Subsequent biochemical, genetic, and phylogenetic studies established that many of these molecules play key roles in essential RNA processing reactions within the nucleus and nucleolus
, including RNA splicing
, polyadenylation
, and the maturation of ribosomal RNA
s.
, and revealed highly complex, compact three dimensional structures consisting of tertiary interactions laid upon the basic cloverleaf secondary structure. Key features of tRNA tertiary structure include the coaxial stacking of adjacent helices and non-Watson-Crick interactions among nucleotides within the apical loops. Additional crystallographic studies showed that a wide range of RNA molecules (including ribozymes, riboswitches and ribosomal RNA
) also fold into specific structures containing a variety of 3D structural motifs. The ability of RNA molecules to adopt specific tertiary structures is essential for their biological activity, and results from the single-stranded nature of RNA. In many ways, RNA folding is more highly analogous to the folding of proteins rather than to the highly repetitive folded structure of the DNA double helix.
molecules showed that they are often much smaller than the DNA sequences that encode them. The genes were shown to be discontinuous, composed of sequences that are not present in the final mature RNA (introns), located between sequences that are retained in the mature RNA (exons). Introns were shown to be removed after transcription through a process termed RNA splicing
. Splicing of RNA transcripts requires a highly precise and coordinated sequence of molecular events, consisting of (a) definition of boundaries between exons and introns, (b) RNA strand cleavage at exactly those sites, and (c) covalent linking (ligation) of the RNA exons in the correct order. The discovery of discontinuous genes and RNA splicing was entirely unexpected by the community of RNA biologists, and stands as one of the most shocking findings in molecular biology research.
is that a single gene
can encode a number of different protein isoforms that can exhibit a variety of (usually related) biological functions. Indeed, most of the proteins encoded by the human genome are generated by alternative splicing.
could be spliced in vitro
. Subsequent biochemical analysis shows that this group I intron was self-splicing; that is, the precursor RNA is capable of carrying out the complete splicing reaction in the absence of proteins. In separate work, the RNA component of the bacterial enzyme ribonuclease P (a ribonucleoprotein
complex) was shown to catalyze its tRNA-processing reaction in the absence of proteins. These experiments represented landmarks in RNA biology, since they revealed that RNA could play an active role in cellular processes, by catalyzing specific biochemical reactions. Before these discoveries, it was believed that biological catalysis was solely the realm of protein
enzymes.
, a proposal that RNA may have played a critical role in prebiotic evolution at a time before the molecules with more specialized functions (DNA and proteins) came to dominate biological information coding and catalysis. Although it is not possible for us to know the course of prebiotic evolution with any certainty, the presence of functional RNA molecules with common ancestry in all modern-day life forms is a strong argument that RNA was widely present at the time of the last common ancestor.
. Some mobile introns encode homing endonucleases, enzymes that initiate the homing process by specifically cleaving double-stranded DNA at or near the intron-insertion site of alleles lacking an intron. Mobile introns are frequently members of either the group I or group II
families of self-splicing introns.
complexes made up of snRNA and protein molecules whose composition and molecular interactions change during the course of the RNA splicing
reactions. Spliceosomes assemble on and around splice sites (the boundaries between introns and exons in the unspliced pre-mRNA) in mRNA precursors and use RNA-RNA interactions to identify critical nucleotide sequences and, probably, to catalyze the splicing reactions. Nuclear pre-mRNA introns and spliceosome-associated snRNAs show similar structural features to self-splicing group II introns. In addition, the splicing pathway of nuclear pre-mRNA introns and group II introns shares a similar reaction pathway. These similarities have led to the hypothesis that these molecules may share a common ancestor.
before being translated into protein. In this process, non-encoded nucleotides may be inserted into specific sites in the RNA, and encoded nucleotides may be removed or replaced. RNA editing
was first discovered within the mitochondria of kinetoplastid
protozoans, where it has been shown to be extensive. For example, some protein-coding genes encode fewer than 50% of the nucleotides found within the mature, translated mRNA. Other RNA editing events are found in mammals, plants, bacteria and viruses. These latter editing events involve fewer nucleotide modifications, insertions and deletions than the events within kinetoplast
DNA, but still have high biological significance for gene expression and its regulation.
enzyme that contains an RNA component that serves as a template strand, and a protein component that has reverse transcriptase
activity and adds nucleotides to the chromosome ends using the internal RNA template.
were responsible for peptidyl transferase
function during translation, because the covalent linking of amino acids represents one of the most central chemical reactions in all of biology. Careful biochemical studies showed that extensively-deproteinized large ribosomal subunits could still catalyze peptide bond formation, thereby implying that the sought-after activity might lie within ribosomal RNA rather than ribosomal proteins. Structural biologists, using X-ray crystallography
, localized the peptidyl transferase center of the ribosome to a highly-conserved
region of the large subunit ribosomal RNA
(rRNA) that is located at the place within the ribosome where the amino-acid-bearing ends of tRNA bind, and where no proteins are present. These studies led to the conclusion that the ribosome
is a ribozyme
. The rRNA sequences that make up the ribosomal active site
represent some of the most highly conserved sequences in the biological world. Together, these observations indicate that peptide bond formation catalyzed by RNA was a feature of the last common ancestor
of all known forms of life.
). These experiments have been used for isolating RNA molecules with a wide range of properties, from binding to particular proteins, to catalyzing particular reactions, to binding low molecular weight organic ligands. They have equal applicability to elucidating interactions and mechanisms that are known properties of naturally-occurring RNA molecules to isolating RNA molecules with biochemical properties that are not known in nature. In developing in vitro selection technology for RNA, laboratory systems for synthesizing complex populations of RNA molecules were established, and used in conjunction with the selection of molecules with user-specified biochemical activities, and in vitro schemes for RNA replication. These steps can be viewed as (a) mutation
, (b) selection, and (c) replication
. Together, then, these three processes enable in vitro molecular evolution
.
(transposons) are found which can replicate via transcription into an RNA intermediate
which is subsequently converted to DNA by reverse transcriptase. These sequences, many of which are likely related to retroviruses, constitute much of the DNA of the eukaryotic nucleus, especially so in plants. Genomic sequencing shows that retrotransposons make up 36% of the human genome and over half of the genome of major cereal crops (wheat and maize).
es change their folded structure in response to environmental conditions (e.g. ambient temperature or concentrations of specific metabolites), and the structural change controls the translation or stability of the mRNA in which the riboswitch is embedded. In this way, gene expression can be dramatically regulated at the post-transcriptional level.
(siRNA) are abundant in eukaryotic cells and exert post-transcriptional control over mRNA expression. They function by binding to specific sites within the mRNA and inducing cleavage of the mRNA via a specific silencing-associated RNA degradation pathway.
s (piRNAs) prevent genome instability in germ line cells, while Xist (X-inactive-specific-transcript) is essential for X-chromosome inactivation in mammals.
Biology
Biology is a natural science concerned with the study of life and living organisms, including their structure, function, growth, origin, evolution, distribution, and taxonomy. Biology is a vast subject containing many subdivisions, topics, and disciplines...
have emerged from studies of RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
(ribonucleic acid), including seminal work in the fields of biochemistry
Biochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
, genetics
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
, microbiology
Microbiology
Microbiology is the study of microorganisms, which are defined as any microscopic organism that comprises either a single cell , cell clusters or no cell at all . This includes eukaryotes, such as fungi and protists, and prokaryotes...
, molecular biology
Molecular biology
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...
, molecular evolution
Molecular evolution
Molecular evolution is in part a process of evolution at the scale of DNA, RNA, and proteins. Molecular evolution emerged as a scientific field in the 1960s as researchers from molecular biology, evolutionary biology and population genetics sought to understand recent discoveries on the structure...
and structural biology
Structural biology
Structural biology is a branch of molecular biology, biochemistry, and biophysics concerned with the molecular structure of biological macromolecules, especially proteins and nucleic acids, how they acquire the structures they have, and how alterations in their structures affect their function...
. As of 2010, 30 scientists have been awarded Nobel Prize
Nobel Prize
The Nobel Prizes are annual international awards bestowed by Scandinavian committees in recognition of cultural and scientific advances. The will of the Swedish chemist Alfred Nobel, the inventor of dynamite, established the prizes in 1895...
s for experimental work that includes studies of RNA. Specific discoveries of high biological significance are discussed in this article.
For related information, see the articles on History of Molecular Biology
History of molecular biology
The history of molecular biology begins in the 1930s with the convergence of various, previously distinct biological disciplines: biochemistry, genetics, microbiology, and virology...
and History of Genetics
History of genetics
The history of genetics started with the work of the Augustinian friar Gregor Johann Mendel. His work on pea plants, published in 1866, described what came to be known as Mendelian Inheritance...
. For background information, see the articles on RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
and nucleic acid
Nucleic acid
Nucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...
.
RNA and DNA have distinct chemical properties
When first studied in the early 1900s, the chemical and biological differences between RNA and DNA were not apparent, and they were named after the materials from which they were isolated; RNA was initially known as "yeastYeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...
nucleic acid" and DNA was "pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
nucleic acid". Using diagnostic chemical tests, carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
chemists showed that the two nucleic acids contained different sugars, whereupon the common name for RNA became "ribose nucleic acid". Other early biochemical studies showed that RNA was readily broken down at high pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
, while DNA was stable (although denatured) in alkali
Alkali
In chemistry, an alkali is a basic, ionic salt of an alkali metal or alkaline earth metal element. Some authors also define an alkali as a base that dissolves in water. A solution of a soluble base has a pH greater than 7. The adjective alkaline is commonly used in English as a synonym for base,...
. Nucleoside composition analysis showed first that RNA contained similar nucleobase
Nucleobase
Nucleobases are a group of nitrogen-based molecules that are required to form nucleotides, the basic building blocks of DNA and RNA. Nucleobases provide the molecular structure necessary for the hydrogen bonding of complementary DNA and RNA strands, and are key components in the formation of stable...
s to DNA, with uracil
Uracil
Uracil is one of the four nucleobases in the nucleic acid of RNA that are represented by the letters A, G, C and U. The others are adenine, cytosine, and guanine. In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced by thymine.Uracil is a common and...
instead of thymine
Thymine
Thymine is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nucleobase. As the name suggests, thymine may be derived by methylation of uracil at...
, and that RNA contained a number of minor nucleobase components, e.g. small amounts of pseudouridine
Pseudouridine
Pseudouridine is the C-glycoside isomer of the nucleoside uridine, and it is the most prevalent of the over one hundred different modified nucleosides found in RNA. Ψ is found in all species and in many classes of RNA except mRNA...
and dimethylguanine.
Messenger RNA (mRNA) carries genetic information that directs protein synthesis
The concept of messenger RNA emerged during the late 1950s, and is associated with CrickFrancis Crick
Francis Harry Compton Crick OM FRS was an English molecular biologist, biophysicist, and neuroscientist, and most noted for being one of two co-discoverers of the structure of the DNA molecule in 1953, together with James D. Watson...
's description of his "Central Dogma of Molecular Biology", which asserted that DNA led to the formation of RNA, which in turn led to the synthesis of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s. During the early 1960s, sophisticated genetic analysis of mutations in the lac operon
Lac operon
The lac operon is an operon required for the transport and metabolism of lactose in Escherichia coli and some other enteric bacteria. It consists of three adjacent structural genes, lacZ, lacY and lacA. The lac operon is regulated by several factors including the availability of glucose and of...
of E. coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
and in the rII locus of bacteriophage T4
Enterobacteria phage T4
Enterobacteria phage T4 is a bacteriophage that infects E. coli bacteria. Its DNA is 169–170 kbp long, and is held in an icosahedral head. T4 is a relatively large phage, at approximately 90 nm wide and 200 nm long...
were instrumental in defining the nature of both messenger RNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
and the genetic code
Genetic code
The genetic code is the set of rules by which information encoded in genetic material is translated into proteins by living cells....
. The short-lived nature of bacterial RNAs, together with the highly complex nature of the cellular mRNA population, made the biochemical isolation of mRNA very challenging. This problem was overcome in the 1960s by the use of reticulocyte
Reticulocyte
Reticulocytes are immature red blood cells, typically composing about 1% of the red cells in the human body.Reticulocytes develop and mature in the red bone marrow and then circulate for about a day in the blood stream before developing into mature red blood cells. Like mature red blood cells,...
s in vertebrates, which produce large quantities of mRNA that are highly enriched in RNA encoding alpha- and beta-globin (the two major protein chains of hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
).
Ribosomes make proteins
In the 1950s, results of labeling experiments in rat liver showed that radioactive amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s were found to be associated with "microsomes" (later redefined as ribosomes) very rapidly after administration, and before they became widely incorporated into cellular proteins. Ribosomes were first visualized using electron microscopy, and their ribonucleoprotein components were identified by biophysical methods, chiefly sedimentation analysis within ultracentrifuges capable of generating very high accelerations (equivalent to hundreds of thousands times gravity). Polysomes (multiple ribosomes moving along a single mRNA molecule) were identified in the early 1960s, and their study led to an understanding of how ribosomes proceed to read the mRNA in a 5' to 3' direction, processively generating proteins as they do so.
Transfer RNA (tRNA) is the physical link between RNA and protein
Biochemical fractionation experiments showed that radioactive amino acids were rapidly incorporated into small RNA molecules that remained soluble under conditions where larger RNA-containing particles would precipitate. These molecules were termed soluble (sRNA) and were later renamed transfer RNA (tRNA). Subsequent studies showed that (i) every cell has multiple species of tRNA, each of which is associated with a single specific amino acid, (ii) that there are a matching set of enzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s responsible for linking tRNAs with the correct amino acids, and (iii) that tRNA anticodon sequences form a specific decoding interaction with mRNA codons.
The genetic code is solved
The genetic codeGenetic code
The genetic code is the set of rules by which information encoded in genetic material is translated into proteins by living cells....
consists of the translation of particular nucleotide sequences in mRNA to specific amino acid sequences in proteins (polypeptides). The ability to work out out the genetic code emerged from the convergence of three different areas of study--(i) new methods to generate synthetic RNA molecules of defined composition to serve as artificial mRNAs, (ii) development of in vitro translation systems that could used to translate the synthetic mRNAs into protein, and (iii) experimental and theoretical genetic work which established that the code was written in three letter "words" (codons). Today, our understanding of the genetic code permits the prediction of the amino sequence of the protein products of the tens of thousands of genes whose sequences are being determined in genome studies
Genome Research
Genome Research is a peer-reviewed scientific journal published by Cold Spring Harbor Laboratory Press. The focus of the journal is on genome-wide studies in any organism, including single gene studies that are placed in a genomic context. This scope includes both experimental and computational...
.
RNA polymerase is purified
The biochemical purification and characterization of RNA polymeraseRNA polymerase
RNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...
from the bacterium Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
enabled the understanding of the mechanisms through which RNA polymerase initiates and terminates transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
, and how those processes are regulated to regulate gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
(i.e. turn genes on and off). Following the isolation of E. coli RNA polymerase, the three RNA polymerases of the eukaryotic nucleus were identified, as well as those associated with viruses and organelles. Studies of transcription also led to the identification of many protein factors that influence transcription, including repressors, activators and enhancers. The availability of purified preparations of RNA polymerase permitted investigators to develop a wide range of novel methods for studying RNA in the test tube, and led directly to many of the subsequent key discoveries in RNA biology.
First complete nucleotide sequence of a biological nucleic acid molecule
Although determining the sequence of proteins was becoming somewhat routine, methods for sequencing of nucleic acids were not available until the mid-1960s. In this seminal work, a specific tRNA was purified in substantial quantities, and then sliced into overlapping fragments using a variety of ribonucleases. Analysis of the detailed nucleotide composition of each fragment provided the information necessary to deduce the sequence of the tRNA. Today, the sequence analysis of much larger nucleic acid molecules is highly-automated and enormously faster.Evolutionary variation of homologous RNA sequences reveals folding patterns
Additional tRNA molecules were purified and sequenced. The first comparative sequence analysis was done and revealed that the sequences varied through evolution in such a way that all of the tRNAs could fold into very similar secondary structures (two-dimensional structures) and had identical sequences at numerous positions (e.g. CCA at the 3' end). The radial four-arm structure of tRNA molecules is termed the 'cloverleaf structure', and results from the evolution of sequences with common ancestry and common biological function. Since the discovery of the tRNA cloverleaf, comparative analysis of numerous other homologous RNA molecules has led to the identification of common sequences and folding patterns.First complete genomic nucleotide sequence
The 3569 nucleotide sequence of all of the genes of the RNA bacteriophageBacteriophage
A bacteriophage is any one of a number of viruses that infect bacteria. They do this by injecting genetic material, which they carry enclosed in an outer protein capsid...
MS2 was determined by a large team of researchers over several years, and was reported in a series of scientific papers. These results enabled the analysis of the first complete genome, albeit an extremely tiny one by modern standards. Several surprising features were identified, including genes that partially overlap one another and the first clues that different organisms might have slightly different codon usage patterns.
Reverse transcriptase can copy RNA into DNA
Retroviruses were shown to have a single-stranded RNA genome and to replicate via a DNA intermediate, the reverse of the usual DNA-to-RNA transcription pathway. They encode a RNA-dependent DNA polymerase (reverse transcriptaseReverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
) that is essential for this process. Some retroviruses can cause diseases, including several that are associated with cancer, and HIV-1 which causes AIDS. Reverse transcriptase has been widely used as an experimental tool for the analysis of RNA molecules in the laboratory, in particular the conversion of RNA molecules into DNA prior to molecular cloning
Molecular cloning
Molecular cloning refers to a set of experimental methods in molecular biology that are used to assemble recombinant DNA molecules and to direct their replication within host organisms...
and/or polymerase chain reaction
Polymerase chain reaction
The polymerase chain reaction is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence....
(PCR).
RNA replicons evolve rapidly
Biochemical and genetic analyses showed that the enzyme systems that replicate viral RNA molecules (reverse transcriptases and RNA replicases) lack molecular proofreading (3' to 5' exonuclease) activity, and that RNA sequences do not benefit from extensive repair systems analogous to those that exist for maintaining and repairing DNA sequences. Consequently, RNA genomes appear to be subject to significantly higher mutation rates than DNA genomes. For example, mutations in HIV-1 that lead to the emergence of viral mutants that are insensitive to antiviral drugs are common, and constitute a major clinical challenge.Ribosomal RNA (rRNA) sequences provide a record of the evolutionary history of all life forms
Analysis of ribosomal RNARibosomal RNA
Ribosomal ribonucleic acid is the RNA component of the ribosome, the enzyme that is the site of protein synthesis in all living cells. Ribosomal RNA provides a mechanism for decoding mRNA into amino acids and interacts with tRNAs during translation by providing peptidyl transferase activity...
sequences from a large number of organisms demonstrated that all extant forms of life on Earth share common structural and sequence features of the ribosomal RNA, reflecting a common ancestry. Mapping the similarities and differences among rRNA molecules from different sources provides clear and quantitative information about the phylogenetic (i.e. evolutionary) relationships among organisms. Analysis of rRNA molecules led to the identification of a third major kingdom of organisms, the archaea
Archaea
The Archaea are a group of single-celled microorganisms. A single individual or species from this domain is called an archaeon...
, in addition to the prokaryotes and eukaryotes.
Non-encoded nucleotides are added to the ends of RNA molecules
Molecular analysis of mRNA molecules showed that, following transcription, mRNAs have non-DNA-encoded nucleotides added to both their 5' and 3' ends (guanosine caps and poly-A, respectively). Enzymes were also identified that add and maintain the universal CCA sequence on the 3' end of tRNA molecules. These events are among the first discovered examples of RNA processing, a complex series of reactions that are needed to convert RNA primary transcripts into biologically active RNA molecules.Small RNA molecules are abundant in the eukaryotic nucleus
Small nuclear RNASmall nuclear RNA
Small nuclear ribonucleic acid is a class of small RNA molecules that are found within the nucleus of eukaryotic cells. They are transcribed by RNA polymerase II or RNA polymerase III and are involved in a variety of important processes such as RNA splicing , regulation of transcription factors ...
molecules (snRNAs) were identified in the eukaryotic nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
using immunological studies with autoimmune antibodies, which bind to small nuclear ribonucleoprotein
SnRNP
snRNPs , or small nuclear ribonucleoproteins, are RNA-protein complexes that combine with unmodified pre-mRNA and various other proteins to form a spliceosome, a large RNA-protein molecular complex upon which splicing of pre-mRNA occurs...
complexes (snRNPs; complexes of the snRNA and protein). Subsequent biochemical, genetic, and phylogenetic studies established that many of these molecules play key roles in essential RNA processing reactions within the nucleus and nucleolus
Nucleolus
The nucleolus is a non-membrane bound structure composed of proteins and nucleic acids found within the nucleus. Ribosomal RNA is transcribed and assembled within the nucleolus...
, including RNA splicing
RNA splicing
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
, polyadenylation
Polyadenylation
Polyadenylation is the addition of a poly tail to an RNA molecule. The poly tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In eukaryotes, polyadenylation is part of the process that produces mature messenger RNA for translation...
, and the maturation of ribosomal RNA
Ribosomal RNA
Ribosomal ribonucleic acid is the RNA component of the ribosome, the enzyme that is the site of protein synthesis in all living cells. Ribosomal RNA provides a mechanism for decoding mRNA into amino acids and interacts with tRNAs during translation by providing peptidyl transferase activity...
s.
RNA molecules require a specific, complex three-dimensional structure for activity
The detailed three-dimensional structure of tRNA molecules was determined using X-ray crystallographyX-ray crystallography
X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...
, and revealed highly complex, compact three dimensional structures consisting of tertiary interactions laid upon the basic cloverleaf secondary structure. Key features of tRNA tertiary structure include the coaxial stacking of adjacent helices and non-Watson-Crick interactions among nucleotides within the apical loops. Additional crystallographic studies showed that a wide range of RNA molecules (including ribozymes, riboswitches and ribosomal RNA
Ribosomal RNA
Ribosomal ribonucleic acid is the RNA component of the ribosome, the enzyme that is the site of protein synthesis in all living cells. Ribosomal RNA provides a mechanism for decoding mRNA into amino acids and interacts with tRNAs during translation by providing peptidyl transferase activity...
) also fold into specific structures containing a variety of 3D structural motifs. The ability of RNA molecules to adopt specific tertiary structures is essential for their biological activity, and results from the single-stranded nature of RNA. In many ways, RNA folding is more highly analogous to the folding of proteins rather than to the highly repetitive folded structure of the DNA double helix.
Genes are commonly interrupted by introns that must be removed by RNA splicing
Analysis of mature eukaryotic messenger RNAMessenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
molecules showed that they are often much smaller than the DNA sequences that encode them. The genes were shown to be discontinuous, composed of sequences that are not present in the final mature RNA (introns), located between sequences that are retained in the mature RNA (exons). Introns were shown to be removed after transcription through a process termed RNA splicing
RNA splicing
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
. Splicing of RNA transcripts requires a highly precise and coordinated sequence of molecular events, consisting of (a) definition of boundaries between exons and introns, (b) RNA strand cleavage at exactly those sites, and (c) covalent linking (ligation) of the RNA exons in the correct order. The discovery of discontinuous genes and RNA splicing was entirely unexpected by the community of RNA biologists, and stands as one of the most shocking findings in molecular biology research.
Alternative pre-mRNA splicing generates multiple proteins from a single gene
The great majority of protein-coding genes encoded within the nucleus of metazoan cells contain multiple introns. In many cases, these introns were shown to be processed in more than one pattern, thus generating a family of related mRNAs that differ, for example, by the inclusion or exclusion of particular exons. The end result of alternative splicingAlternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
is that a single gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
can encode a number of different protein isoforms that can exhibit a variety of (usually related) biological functions. Indeed, most of the proteins encoded by the human genome are generated by alternative splicing.
Discovery of catalytic RNA (ribozymes)
An experimental system was developed in which an intron-containing rRNA precursor from the nucleus of the ciliated protozoan TetrahymenaTetrahymena
Tetrahymena are free-living ciliate protozoa that can also switch from commensalistic to pathogenic modes of survival. They are common in fresh-water. Tetrahymena species used as model organisms in biomedical research are T. thermophila and T. pyriformis.- T...
could be spliced in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
. Subsequent biochemical analysis shows that this group I intron was self-splicing; that is, the precursor RNA is capable of carrying out the complete splicing reaction in the absence of proteins. In separate work, the RNA component of the bacterial enzyme ribonuclease P (a ribonucleoprotein
Ribonucleoprotein
Ribonucleoprotein is a nucleoprotein that contains RNA, i.e. it is an association that combines ribonucleic acid and protein together. A few known examples include the ribosome, the enzyme telomerase, vault ribonucleoproteins, and small nuclear RNPs , which are implicated in pre-mRNA splicing and...
complex) was shown to catalyze its tRNA-processing reaction in the absence of proteins. These experiments represented landmarks in RNA biology, since they revealed that RNA could play an active role in cellular processes, by catalyzing specific biochemical reactions. Before these discoveries, it was believed that biological catalysis was solely the realm of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
enzymes.
RNA was likely critical for prebiotic evolution
The discovery of catalytic RNA (ribozymes) showed that RNA could both encode genetic information (like DNA) and catalyze specific biochemical reactions (like protein enzymes). This realization led to the RNA World HypothesisRNA world hypothesis
The RNA world hypothesis proposes that life based on ribonucleic acid pre-dates the current world of life based on deoxyribonucleic acid , RNA and proteins. RNA is able both to store genetic information, like DNA, and to catalyze chemical reactions, like an enzyme protein...
, a proposal that RNA may have played a critical role in prebiotic evolution at a time before the molecules with more specialized functions (DNA and proteins) came to dominate biological information coding and catalysis. Although it is not possible for us to know the course of prebiotic evolution with any certainty, the presence of functional RNA molecules with common ancestry in all modern-day life forms is a strong argument that RNA was widely present at the time of the last common ancestor.
Introns can be mobile genetic elements
Some self-splicing introns can spread through a population of organisms by "homing", inserting copies of themselves into genes at sites that previously lacked an intron. Because they are self-splicing (that is, they remove themselves at the RNA level from genes into which they have inserted), these sequences represent transposons that are genetically silent, i.e. they do not interfere with the expression of the gene into which they become inserted. These introns can be regarded as examples of selfish DNASelfish DNA
Selfish DNA refers to those sequences of DNA which, in their purest form, have two distinct properties: the DNA sequence spreads by forming additional copies of itself within the genome; and it makes no specific contribution to the reproductive success of its host organism.This idea was sketched...
. Some mobile introns encode homing endonucleases, enzymes that initiate the homing process by specifically cleaving double-stranded DNA at or near the intron-insertion site of alleles lacking an intron. Mobile introns are frequently members of either the group I or group II
Group II intron
Group II introns are a large class of self-catalytic ribozymes as well as mobile genetic element found within the genes of all three domains of life. Ribozyme activity can occur under high-salt conditions in vitro. However, assistance from proteins is required for in vivo splicing...
families of self-splicing introns.
Spliceosomes mediate nuclear pre-mRNA splicing
Introns are removed from nuclear pre-mRNAs by splicesomes, large ribonucleoproteinRibonucleoprotein
Ribonucleoprotein is a nucleoprotein that contains RNA, i.e. it is an association that combines ribonucleic acid and protein together. A few known examples include the ribosome, the enzyme telomerase, vault ribonucleoproteins, and small nuclear RNPs , which are implicated in pre-mRNA splicing and...
complexes made up of snRNA and protein molecules whose composition and molecular interactions change during the course of the RNA splicing
RNA splicing
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
reactions. Spliceosomes assemble on and around splice sites (the boundaries between introns and exons in the unspliced pre-mRNA) in mRNA precursors and use RNA-RNA interactions to identify critical nucleotide sequences and, probably, to catalyze the splicing reactions. Nuclear pre-mRNA introns and spliceosome-associated snRNAs show similar structural features to self-splicing group II introns. In addition, the splicing pathway of nuclear pre-mRNA introns and group II introns shares a similar reaction pathway. These similarities have led to the hypothesis that these molecules may share a common ancestor.
RNA sequences can be edited within cells
Messenger RNA precursors from a wide range of organisms can be editedRNA editing
The term RNA editing describes those molecular processes in which the information content in an RNA molecule is altered through a chemical change in the base makeup. To date, such changes have been observed in tRNA, rRNA, mRNA and microRNA molecules of eukaryotes but not prokaryotes...
before being translated into protein. In this process, non-encoded nucleotides may be inserted into specific sites in the RNA, and encoded nucleotides may be removed or replaced. RNA editing
RNA editing
The term RNA editing describes those molecular processes in which the information content in an RNA molecule is altered through a chemical change in the base makeup. To date, such changes have been observed in tRNA, rRNA, mRNA and microRNA molecules of eukaryotes but not prokaryotes...
was first discovered within the mitochondria of kinetoplastid
Kinetoplastid
The kinetoplastids are a group of single-cell flagellate protozoa, including a number of parasites responsible for serious diseases in humans and other animals, as well as various forms found in soil and aquatic environments...
protozoans, where it has been shown to be extensive. For example, some protein-coding genes encode fewer than 50% of the nucleotides found within the mature, translated mRNA. Other RNA editing events are found in mammals, plants, bacteria and viruses. These latter editing events involve fewer nucleotide modifications, insertions and deletions than the events within kinetoplast
Kinetoplast
A kinetoplast is a disk-shaped mass of circular DNA inside a large mitochondrion that contains many copies of the mitochondrial genome. Kinetoplasts are only found in protozoa of the class Kinetoplastida...
DNA, but still have high biological significance for gene expression and its regulation.
Telomerase uses a built-in RNA template to maintain chromosome ends
Telomerase is an enzyme that is present in all eukaryotic nuclei which serves to maintain the ends of the linear DNA in the linear chromosomes of the eukaryotic nucleus, through the addition of terminal sequences that are lost in each round of DNA replication. Before telomerase was identified, its activity was predicted on the basis of a molecular understanding of DNA replication, which indicated that the DNA polymerases known at that time could not replicate the 3' end of a linear chromosome, due to the absence of a template strand. Telomerase was shown to be a ribonucleoproteinRibonucleoprotein
Ribonucleoprotein is a nucleoprotein that contains RNA, i.e. it is an association that combines ribonucleic acid and protein together. A few known examples include the ribosome, the enzyme telomerase, vault ribonucleoproteins, and small nuclear RNPs , which are implicated in pre-mRNA splicing and...
enzyme that contains an RNA component that serves as a template strand, and a protein component that has reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
activity and adds nucleotides to the chromosome ends using the internal RNA template.
Ribosomal RNA catalyzes peptide bond formation
For years, scientists had worked to identify which protein(s) within the ribosomeRibosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....
were responsible for peptidyl transferase
Peptidyl transferase
The Peptidyl transferase is an aminoacyltransferase as well as the primary enzymatic function of the ribosome, which forms peptide links between adjacent amino acids using tRNAs during the translation process of protein biosynthesis....
function during translation, because the covalent linking of amino acids represents one of the most central chemical reactions in all of biology. Careful biochemical studies showed that extensively-deproteinized large ribosomal subunits could still catalyze peptide bond formation, thereby implying that the sought-after activity might lie within ribosomal RNA rather than ribosomal proteins. Structural biologists, using X-ray crystallography
X-ray crystallography
X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...
, localized the peptidyl transferase center of the ribosome to a highly-conserved
Conserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...
region of the large subunit ribosomal RNA
Ribosomal RNA
Ribosomal ribonucleic acid is the RNA component of the ribosome, the enzyme that is the site of protein synthesis in all living cells. Ribosomal RNA provides a mechanism for decoding mRNA into amino acids and interacts with tRNAs during translation by providing peptidyl transferase activity...
(rRNA) that is located at the place within the ribosome where the amino-acid-bearing ends of tRNA bind, and where no proteins are present. These studies led to the conclusion that the ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....
is a ribozyme
Ribozyme
A ribozyme is an RNA molecule with a well defined tertiary structure that enables it to catalyze a chemical reaction. Ribozyme means ribonucleic acid enzyme. It may also be called an RNA enzyme or catalytic RNA. Many natural ribozymes catalyze either the hydrolysis of one of their own...
. The rRNA sequences that make up the ribosomal active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
represent some of the most highly conserved sequences in the biological world. Together, these observations indicate that peptide bond formation catalyzed by RNA was a feature of the last common ancestor
Last universal ancestor
The last universal ancestor , also called the last universal common ancestor , or the cenancestor, is the most recent organism from which all organisms now living on Earth descend. Thus it is the most recent common ancestor of all current life on Earth...
of all known forms of life.
Combinatorial selection of RNA molecules enables in vitro evolution
Experimental methods were invented that allowed investigators to use large, diverse populations of RNA molecules to carry out in vitro molecular experiments that utilized powerful selective replication strategies used by geneticists, and which amount to evolution in the test tube. These experiments have been described using different names, the most common of which are "combinatorial selection", "in vitro selection", and SELEX (for Systematic Evolution of Ligands by Exponential EnrichmentSystematic Evolution of Ligands by Exponential Enrichment
SELEX , also referred to as in vitro selection or in vitro evolution, is a combinatorial chemistry technique in molecular biology for producing oligonucleotides of either single-stranded DNA or RNA that specifically bind to a target ligand or ligands....
). These experiments have been used for isolating RNA molecules with a wide range of properties, from binding to particular proteins, to catalyzing particular reactions, to binding low molecular weight organic ligands. They have equal applicability to elucidating interactions and mechanisms that are known properties of naturally-occurring RNA molecules to isolating RNA molecules with biochemical properties that are not known in nature. In developing in vitro selection technology for RNA, laboratory systems for synthesizing complex populations of RNA molecules were established, and used in conjunction with the selection of molecules with user-specified biochemical activities, and in vitro schemes for RNA replication. These steps can be viewed as (a) mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
, (b) selection, and (c) replication
Self-replication
Self-replication is any behavior of a dynamical system that yields construction of an identical copy of that dynamical system. Biological cells, given suitable environments, reproduce by cell division. During cell division, DNA is replicated and can be transmitted to offspring during reproduction...
. Together, then, these three processes enable in vitro molecular evolution
Molecular evolution
Molecular evolution is in part a process of evolution at the scale of DNA, RNA, and proteins. Molecular evolution emerged as a scientific field in the 1960s as researchers from molecular biology, evolutionary biology and population genetics sought to understand recent discoveries on the structure...
.
Many mobile DNA elements use an RNA intermediate
Transposable genetic elementsTransposon
Transposable elements are sequences of DNA that can move or transpose themselves to new positions within the genome of a single cell. The mechanism of transposition can be either "copy and paste" or "cut and paste". Transposition can create phenotypically significant mutations and alter the cell's...
(transposons) are found which can replicate via transcription into an RNA intermediate
Retrotransposon
Retrotransposons are genetic elements that can amplify themselves in a genome and are ubiquitous components of the DNA of many eukaryotic organisms. They are a subclass of transposon. They are particularly abundant in plants, where they are often a principal component of nuclear DNA...
which is subsequently converted to DNA by reverse transcriptase. These sequences, many of which are likely related to retroviruses, constitute much of the DNA of the eukaryotic nucleus, especially so in plants. Genomic sequencing shows that retrotransposons make up 36% of the human genome and over half of the genome of major cereal crops (wheat and maize).
Riboswitches bind cellular metabolites and control gene expression
Segments of RNA, typically embedded within the 5'-untranslated region of a vast number of bacterial mRNA molecules, have a profound effect on gene expression through a previously-undiscovered mechanism that does not involve the participation of proteins. In many cases, riboswitchRiboswitch
In molecular biology, a riboswitch is a part of an mRNA molecule that can directly bind a small target molecule, and whose binding of the target affects the gene's activity. Thus, an mRNA that contains a riboswitch is directly involved in regulating its own activity, in response to the...
es change their folded structure in response to environmental conditions (e.g. ambient temperature or concentrations of specific metabolites), and the structural change controls the translation or stability of the mRNA in which the riboswitch is embedded. In this way, gene expression can be dramatically regulated at the post-transcriptional level.
Small RNA molecules regulate gene expression by post-transcriptional gene silencing
Another previously unknown mechanism by which RNA molecules are involved in genetic regulation was discovered in the 1990s. Small RNA molecules termed microRNA (miRNA) and small interfering RNARNA interference
RNA interference is a process within living cells that moderates the activity of their genes. Historically, it was known by other names, including co-suppression, post transcriptional gene silencing , and quelling. Only after these apparently unrelated processes were fully understood did it become...
(siRNA) are abundant in eukaryotic cells and exert post-transcriptional control over mRNA expression. They function by binding to specific sites within the mRNA and inducing cleavage of the mRNA via a specific silencing-associated RNA degradation pathway.
Noncoding RNA controls epigenetic phenomena
In addition to their well-established roles in translation and splicing, members of noncoding RNA (ncRNA) families have recently been found to function in genome defense and chromosome inactivation. For example, piwi-interacting RNAPiwi-interacting RNA
Piwi-interacting RNA is the largest class of small non-coding RNA molecules that is expressed in animal cells. piRNAs form RNA-protein complexes through interactions with piwi proteins...
s (piRNAs) prevent genome instability in germ line cells, while Xist (X-inactive-specific-transcript) is essential for X-chromosome inactivation in mammals.
Nobel Laureates in RNA biology
| Name | Dates | Institution | Awards |
|---|---|---|---|
| Altman, Sidney Sidney Altman Sidney Altman is a Canadian American molecular biologist, who is currently the Sterling Professor of Molecular, Cellular, and Developmental Biology and Chemistry at Yale University. In 1989 he shared the Nobel Prize in Chemistry with Thomas R... |
1939- | Yale University Yale University Yale University is a private, Ivy League university located in New Haven, Connecticut, United States. Founded in 1701 in the Colony of Connecticut, the university is the third-oldest institution of higher education in the United States... |
1989 Nobel Prize in Chemistry |
| Baltimore, David David Baltimore David Baltimore is an American biologist, university administrator, and Nobel laureate in Physiology or Medicine. He served as president of the California Institute of Technology from 1997 to 2006, and is currently the Robert A. Millikan Professor of Biology at Caltech... |
1938- | California Institute of Technology California Institute of Technology The California Institute of Technology is a private research university located in Pasadena, California, United States. Caltech has six academic divisions with strong emphases on science and engineering... |
1975 Nobel Prize in Physiology or Medicine |
| Barré-Sinoussi, Françoise Françoise Barré-Sinoussi Françoise Barré-Sinoussi is a French virologist and director of the Unité de Régulation des Infections Rétrovirales at the Institut Pasteur in Paris, France. Born in Paris, France, Barré-Sinoussi performed some of the fundamental work in the identification of the human immunodeficiency virus as... |
1947- | Pasteur Institute Pasteur Institute The Pasteur Institute is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who made some of the greatest breakthroughs in modern medicine at the time, including pasteurization and vaccines for anthrax... |
2008 Nobel Prize in Physiology or Medicine |
| Blackburn, Elizabeth Elizabeth Blackburn Elizabeth Helen Blackburn, AC, FRS is an Australian-born American biological researcher at the University of California, San Francisco, who studies the telomere, a structure at the end of chromosomes that protects the chromosome. Blackburn co-discovered telomerase, the enzyme that replenishes the... |
1948- | University of California, San Francisco University of California, San Francisco The University of California, San Francisco is one of the world's leading centers of health sciences research, patient care, and education. UCSF's medical, pharmacy, dentistry, nursing, and graduate schools are among the top health science professional schools in the world... |
2009 Nobel Prize in Physiology or Medicine |
| Brenner, Sydney Sydney Brenner Sydney Brenner, CH FRS is a South African biologist and a 2002 Nobel prize in Physiology or Medicine laureate, shared with H... |
1927- | Salk Institute | 2002 Nobel Prize in Physiology or Medicine |
| Cech, Thomas Thomas Cech Thomas Robert Cech is a chemist who shared the 1989 Nobel prize in chemistry with Sidney Altman, for their discovery of the catalytic properties of RNA. Cech discovered that RNA could itself cut strands of RNA, which showed that life could have started as RNA... |
1947- | University of Colorado, Boulder | 1989 Nobel Prize in Chemistry |
| Crick, Francis Francis Crick Francis Harry Compton Crick OM FRS was an English molecular biologist, biophysicist, and neuroscientist, and most noted for being one of two co-discoverers of the structure of the DNA molecule in 1953, together with James D. Watson... |
1916–2004 | Salk Institute | 1962 Nobel Prize in Physiology or Medicine |
| Dulbecco, Renato Renato Dulbecco Renato Dulbecco is an Italian virologist who won a 1975 Nobel Prize in Physiology or Medicine for his work on reverse transcriptase. In 1973 he was awarded the Louisa Gross Horwitz Prize from Columbia University together with Theodore Puck and Harry Eagle. Dulbecco was the recipient of the Selman A... |
1914- | CNR Institute of Biomedical Technologies (Italy) | 1975 Nobel Prize in Physiology or Medicine |
| Fire, Andrew Andrew Fire Andrew Zachary Fire is an American biologist and professor of pathology and of genetics at the Stanford University School of Medicine. He was awarded the 2006 Nobel Prize for Physiology or Medicine, along with Craig C. Mello, for the discovery of RNA interference... |
1959- | Stanford University Stanford University The Leland Stanford Junior University, commonly referred to as Stanford University or Stanford, is a private research university on an campus located near Palo Alto, California. It is situated in the northwestern Santa Clara Valley on the San Francisco Peninsula, approximately northwest of San... |
2006 Nobel Prize in Physiology or Medicine |
| Gilbert, Walter Walter Gilbert Walter Gilbert is an American physicist, biochemist, molecular biology pioneer, and Nobel laureate.-Biography:Gilbert was born in Boston, Massachusetts, on March 21, 1932... |
1932- | Harvard University Harvard University Harvard University is a private Ivy League university located in Cambridge, Massachusetts, United States, established in 1636 by the Massachusetts legislature. Harvard is the oldest institution of higher learning in the United States and the first corporation chartered in the country... |
1980 Nobel Prize in Chemistry |
| Greider, Carol Carol W. Greider Carolyn Widney "Carol" Greider is an American molecular biologist. She is Daniel Nathans Professor and Director of Molecular Biology and Genetics at Johns Hopkins University. She discovered the enzyme telomerase in 1984, when she was a graduate student of Elizabeth Blackburn at the University of... |
1961- | Johns Hopkins University Johns Hopkins University The Johns Hopkins University, commonly referred to as Johns Hopkins, JHU, or simply Hopkins, is a private research university based in Baltimore, Maryland, United States... |
2009 Nobel Prize in Physiology or Medicine |
| Holley, Robert Robert W. Holley Robert William Holley was an American biochemist. He shared the Nobel Prize in Physiology or Medicine in 1968 for describing the structure of alanine transfer RNA, linking DNA and protein synthesis.Holley was born in Urbana, Illinois, and graduated from Urbana High School in 1938... |
1922–1993 | Cornell University Cornell University Cornell University is an Ivy League university located in Ithaca, New York, United States. It is a private land-grant university, receiving annual funding from the State of New York for certain educational missions... |
1968 Nobel Prize in Physiology or Medicine |
| Jacob, François François Jacob François Jacob is a French biologist who, together with Jacques Monod, originated the idea that control of enzyme levels in all cells occurs through feedback on transcription. He shared the 1965 Nobel Prize in Medicine with Jacques Monod and André Lwoff.-Childhood and education:François Jacob is... |
1920 | Pasteur Institute Pasteur Institute The Pasteur Institute is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who made some of the greatest breakthroughs in modern medicine at the time, including pasteurization and vaccines for anthrax... |
1965 Nobel Prize in Physiology or Medicine |
| Khorana, H. Gobind | 1922- | Massachusetts Institute of Technology Massachusetts Institute of Technology The Massachusetts Institute of Technology is a private research university located in Cambridge, Massachusetts. MIT has five schools and one college, containing a total of 32 academic departments, with a strong emphasis on scientific and technological education and research.Founded in 1861 in... |
1968 Nobel Prize in Physiology or Medicine |
| Klug, Aaron Aaron Klug Sir Aaron Klug, OM, PRS is a Lithuanian-born British chemist and biophysicist, and winner of the 1982 Nobel Prize in Chemistry for his development of crystallographic electron microscopy and his structural elucidation of biologically important nucleic acid-protein complexes.-Biography:Klug was... |
1926- | Medical Research Council (UK) Medical Research Council (UK) The Medical Research Council is a publicly-funded agency responsible for co-ordinating and funding medical research in the United Kingdom. It is one of seven Research Councils in the UK and is answerable to, although politically independent from, the Department for Business, Innovation and Skills... |
1982 Nobel Prize in Chemistry |
| Kornberg, Roger Roger D. Kornberg Roger David Kornberg is an American biochemist and professor of structural biology at Stanford University School of Medicine.Kornberg was awarded the Nobel Prize in Chemistry in 2006 for his studies of the process by which genetic information from DNA is copied to RNA, "the molecular basis of... |
1947- | Stanford University Stanford University The Leland Stanford Junior University, commonly referred to as Stanford University or Stanford, is a private research university on an campus located near Palo Alto, California. It is situated in the northwestern Santa Clara Valley on the San Francisco Peninsula, approximately northwest of San... |
2006 Nobel Prize in Chemistry |
| Mello, Craig Craig Mello Craig Cameron Mello is a Portuguese-American biologist and Professor of Molecular Medicine at the University of Massachusetts Medical School in Worcester, Massachusetts. He was awarded the 2006 Nobel Prize for Physiology or Medicine, along with Andrew Z. Fire, for the discovery of RNA interference... |
1960- | University of Massachusetts Medical School University of Massachusetts Medical School The University of Massachusetts Medical School is one of five campuses of the University of Massachusetts system and is home to three schools: the School of Medicine, the Graduate School of Biomedical Sciences, the Graduate School of Nursing; a biomedical research enterprise; and a range of... |
2006 Nobel Prize in Physiology or Medicine |
| Monod, Jacques Jacques Monod Jacques Lucien Monod was a French biologist who was awarded a Nobel Prize in Physiology or Medicine in 1965, sharing it with François Jacob and Andre Lwoff "for their discoveries concerning genetic control of enzyme and virus synthesis"... |
1910–1976 | Pasteur Institute Pasteur Institute The Pasteur Institute is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who made some of the greatest breakthroughs in modern medicine at the time, including pasteurization and vaccines for anthrax... |
1965 Nobel Prize in Physiology or Medicine |
| Montagnier, Luc Luc Montagnier Luc Antoine Montagnier is a French virologist and joint recipient with Françoise Barré-Sinoussi and Harald zur Hausen of the 2008 Nobel Prize in Physiology or Medicine, for his discovery of the human immunodeficiency virus... |
1932- | Pasteur Institute Pasteur Institute The Pasteur Institute is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who made some of the greatest breakthroughs in modern medicine at the time, including pasteurization and vaccines for anthrax... |
2008 Nobel Prize in Physiology or Medicine |
| Nirenberg, Marshall Marshall Warren Nirenberg Marshall Warren Nirenberg was an American biochemist and geneticist of Jewish origin. He shared a Nobel Prize in Physiology or Medicine in 1968 with Har Gobind Khorana and Robert W. Holley for "breaking the genetic code" and describing how it operates in protein synthesis... |
1927–2010 | National Institutes of Health (USA) National Institutes of Health The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation... |
1968 Nobel Prize in Physiology or Medicine |
| Ochoa, Severo Severo Ochoa Severo Ochoa de Albornoz was a Spanish-American doctor and biochemist, and joint winner of the 1959 Nobel Prize in Physiology or Medicine with Arthur Kornberg.-Early life:... |
1905–1993 | New York University New York University New York University is a private, nonsectarian research university based in New York City. NYU's main campus is situated in the Greenwich Village section of Manhattan... |
1959 Nobel Prize in Physiology or Medicine |
| Temin, Howard | 1934–1994 | University of Wisconsin, Madison | 1975 Nobel Prize in Physiology or Medicine |
| Ramakrishnan, Venkatraman | 1952- | Medical Research Council (UK) Medical Research Council (UK) The Medical Research Council is a publicly-funded agency responsible for co-ordinating and funding medical research in the United Kingdom. It is one of seven Research Councils in the UK and is answerable to, although politically independent from, the Department for Business, Innovation and Skills... |
2009 Nobel Prize in Chemistry |
| Roberts, Richard Richard J. Roberts Sir Richard "Rich" John Roberts is a British biochemist and molecular biologist. He was awarded the 1993 Nobel Prize in Physiology or Medicine with Phillip Allen Sharp for the discovery of introns in eukaryotic DNA and the mechanism of gene-splicing.When he was 4, his family moved to Bath. In... |
1943- | New England Biolabs New England Biolabs New England Biolabs produces and supplies reagents for the life science industry. NEB offers 230 recombinant and 30 native restriction enzymes for genomic research, as well as nicking enzymes and DNA methylases. It offers products in the areas related to proteomics, DNA Sequencing, and drug... |
1993 Nobel Prize in Physiology or Medicine |
| Sharp, Philip | 1944- | Massachusetts Institute of Technology Massachusetts Institute of Technology The Massachusetts Institute of Technology is a private research university located in Cambridge, Massachusetts. MIT has five schools and one college, containing a total of 32 academic departments, with a strong emphasis on scientific and technological education and research.Founded in 1861 in... |
1993 Nobel Prize in Physiology or Medicine |
| Steitz, Thomas Thomas A. Steitz -Publications:* Steitz, T. A., et al. , nsls newsletter, .* Steitz, T. A., et al. , NSLS Activity Report .-External links:* , from the Office of Scientific and Technical Information, United States Department of Energy... |
1940- | Yale University Yale University Yale University is a private, Ivy League university located in New Haven, Connecticut, United States. Founded in 1701 in the Colony of Connecticut, the university is the third-oldest institution of higher education in the United States... |
2009 Nobel Prize in Chemistry |
| Szostak, Jack Jack W. Szostak Jack William Szostak is a Canadian American biologist of Polish British descent and Professor of Genetics at Harvard Medical School and Alexander Rich Distinguished Investigator at Massachusetts General Hospital, Boston. He was awarded the 2009 Nobel Prize for Physiology or Medicine, along with... |
1952- | Harvard University Harvard University Harvard University is a private Ivy League university located in Cambridge, Massachusetts, United States, established in 1636 by the Massachusetts legislature. Harvard is the oldest institution of higher learning in the United States and the first corporation chartered in the country... |
2009 Nobel Prize in Physiology or Medicine |
| Todd, Alexander Alexander R. Todd, Baron Todd Alexander Robertus Todd, Baron Todd, OM, PRS FRSE was a Scottish biochemist whose research on the structure and synthesis of nucleotides, nucleosides, and nucleotide coenzymes gained him the 1957 Nobel Prize for Chemistry.Todd was born near Glasgow, attended Allan Glen's School and graduated from... |
1907–1997 | University of Cambridge University of Cambridge The University of Cambridge is a public research university located in Cambridge, United Kingdom. It is the second-oldest university in both the United Kingdom and the English-speaking world , and the seventh-oldest globally... |
1957 Nobel Prize in Chemistry |
| Watson, James James D. Watson James Dewey Watson is an American molecular biologist, geneticist, and zoologist, best known as one of the co-discoverers of the structure of DNA in 1953 with Francis Crick... |
1928- | Cold Spring Harbor Laboratory Cold Spring Harbor Laboratory The Cold Spring Harbor Laboratory is a private, non-profit institution with research programs focusing on cancer, neurobiology, plant genetics, genomics and bioinformatics. The Laboratory has a broad educational mission, including the recently established Watson School of Biological Sciences. It... |
1962 Nobel Prize in Physiology or Medicine |
| Yonath, Ada Ada Yonath Ada E. Yonath is an Israeli crystallographer best known for her pioneering work on the structure of the ribosome. She is the current director of the Helen and Milton A. Kimmelman Center for Biomolecular Structure and Assembly of the Weizmann Institute of Science. In 2009, she received the Nobel... |
1939- | Weizmann Institute of Science Weizmann Institute of Science The Weizmann Institute of Science , known as Machon Weizmann, is a university and research institute in Rehovot, Israel. It differs from other Israeli universities in that it offers only graduate and post-graduate studies in the sciences.... |
2009 Nobel Prize in Chemistry |