Non-coding RNA
Encyclopedia
A non-coding RNA is a functional RNA
molecule that is not translated
into a protein
. Less-frequently used synonyms are non-protein-coding RNA (npcRNA), non-messenger RNA (nmRNA) and functional RNA (fRNA). The term small RNA (sRNA) is often used for short bacteria
l ncRNAs. The DNA
sequence from which a non-coding RNA is transcribed is often called an RNA gene
.
Non-coding RNA genes include highly abundant and functionally important RNAs such as transfer RNA
(tRNA) and ribosomal RNA
(rRNA), as well as RNAs such as snoRNA
s, microRNAs, siRNA
s and piRNA
s and the long ncRNA
s that include examples such as Xist and HOTAIR
(see here for a more complete list of ncRNAs). The number of ncRNAs encoded within the human genome is unknown, however recent transcriptomic and bioinformatic studies suggest the existence of thousands of ncRNAs., but see Since many of the newly identified ncRNAs have not been validated for their function, it is possible that many are non-functional.
s were first discovered in 1868 by Friedrich Miescher
and by 1939 RNA had been implicated in protein synthesis
. Two decades later, Francis Crick
predicted a functional RNA component which mediated translation
; he reasoned that RNA is better suited to base-pair with an mRNA transcript than a pure polypeptide.
The first non-coding RNA to be characterised was an alanine
tRNA found in baker's yeast
, its structure was published in 1965. To produce a purified alanine tRNA sample, Robert W. Holley
et al. used 140kg
of commercial baker's yeast to give just 1g
of purified tRNAAla for analysis. The 80 nucleotide
tRNA was sequenced by first being digested with Pancreatic ribonuclease
(producing fragments ending in Cytosine
or Uridine
) and then with takadiastase ribonuclease Tl (producing fragments which finished with Guanosine
). Chromatography
and identification of the 5' and 3' ends then helped arrange the fragments to establish the RNA sequence. Of the three structures originally proposed for this tRNA, the 'cloverleaf' structure was independently proposed in several following publications. The cloverleaf secondary structure
was finalised following X-ray crystallography
anaylsis performed by two independent research groups in 1974.
Ribosomal RNA
was next to be discovered, followed by URNA in the early 1980s. Since then, the discovery of new non-coding RNAs has continued with snoRNAs, Xist, CRISPR
and many more. Recent notable additions include riboswitch
es and miRNA
, the discovery of the RNAi mechanism
associated with the latter earned Craig C. Mello and Andrew Fire
the 2006 Nobel Prize in Physiology or Medicine
.
processes. These range from ncRNAs of central importance that are
conserved across all or most cellular life through to more transient
ncRNAs specific to one or a few closely related species. The more
conserved ncRNAs are thought to be molecular fossils or relics from
LUCA
and the RNA world
.
Many of the conserved, essential and abundant ncRNAs are involved in translation
. Ribonucleoprotein
(RNP) particles called ribosome
s are the 'factories' where translation takes place in the cell. The ribosome consists of more than 60% ribosomal RNA, these are made up of 3 ncRNAs in prokaryotes and 4 ncRNAs in eukaryotes. Ribosomal RNAs catalyse the translation of nucleotide sequences to protein. Another set of ncRNAs, Transfer RNA
s, form an 'adaptor molecule' between mRNA and protein. The H/ACA box and C/D box snoRNAs
are ncRNAs found in archaea and eukaryotes, RNase MRP
is restricted to eukaryotes, both groups of ncRNA are involved in the maturation of rRNA. The snoRNAs guide covalent modifications of rRNA, tRNA and snRNAs, RNase MRP cleaves the internal transcribed spacer 1 between 18S and 5.8S rRNAs. The ubiquitous ncRNA, RNase P
, is an evolutionary relative of RNase MRP. RNase P matures tRNA sequences by generating mature 5'-ends of tRNAs through cleaving the 5'-leader elements of precursor-tRNAs. Another ubiquitous RNP called SRP
recognizes and transports specific nascent proteins to the endoplasmic reticulum
in eukaryote
s and the plasma membrane in prokaryote
s. In bacteria Transfer-messenger RNA
(tmRNA) is an RNP involved in rescuing stalled ribosomes, tagging incomplete polypeptides
and promoting the degradation of aberrant mRNA.
In eukaryotes the spliceosome
performs the splicing
reactions essential
for removing intron
sequences, this process is required for the formation of mature mRNA.
The spliceosome
is another RNP often also known as the snRNP
or tri-snRNP.
There are two different forms of the spliceosome, the major and minor forms.
The ncRNA components of the major spliceosome are U1, U2,
U4, U5, and U6.
The ncRNA components of the minor spliceosome are U11, U12,
U5, U4atac
and
U6atac
.
Another group of introns can catalyse their own removal from host transcripts, these are called self-splicing RNAs.
There are two main groups of self-splicing RNAs, these are the group I catalytic intron
and
group II catalytic intron. These ncRNAs catalyze their own excision from mRNA, tRNA and rRNA precursors in a wide range of organisms.
In mammals it has been found that snoRNAs can also regulate the alternative splicing
of
mRNA, for example snoRNA HBII-52
regulates the splicing of
serotonin receptor 2C
.
In nematodes the SmY ncRNA appears to be involved in mRNA trans-splicing
.
of many thousands of gene
s are regulated by ncRNAs.
This regulation can occur in trans
or in cis.
can reduce the expression levels of hundreds of genes. The mechanism by which mature miRNA molecules
act is through partial complementary to one or more messenger RNA (mRNA) molecules, generally in
3' UTRs
. The main function of miRNAs is to down-regulate
gene expression.
The ncRNA RNase P
has also been shown to influence gene expression.
In the human nucleus RNase P
is required for the
normal and efficient transcription of various ncRNAs transcribed by
RNA polymerase III
. These include tRNA, 5S rRNA
,
SRP
RNA and U6 snRNA
genes. RNase P exerts its role in transcription through association with
Pol III and chromatin
of active tRNA and 5S rRNA genes.
It has been shown that 7SK RNA
, a metazoan ncRNA, acts as a negative regulator of the
RNA polymerase II
elongation factor P-TEFb
, and that this activity is
influenced by stress response pathways.
The bacterial ncRNA, 6S RNA, specifically associates with RNA polymerase holoenzyme
containing the sigma70
specificity factor. This interaction represses
expression from a sigma70-dependent promoter during stationary phase
.
Another bacterial ncRNA, OxyS RNA
represses translation by binding to Shine-Dalgarno sequences thereby occluding ribosome binding. OxyS RNA is induced in response to oxidative stress in Escherichia coli.
The B2 RNA is a small noncoding RNA polymerase III transcript that represses mRNA transcription in response to heat shock in mouse
cells. B2 RNA inhibits transcription by binding to core Pol II. Through this interaction, B2 RNA assembles into preinitiation
complexes at the promoter and blocks RNA synthesis.
A recent study has shown that just the act of transcription of ncRNA
sequence can have an influence on gene expression. RNA polymerase II
transcription of ncRNAs is required for chromatin
remodelling
in the Schizosaccharomyces pombe
. Chromatin is progressively
converted to an open configuration, as several species of ncRNAs are
transcribed.
and influence their expression in various ways. For
example, a riboswitch
can directly
bind a small target molecule
, the binding of the target affects
the gene's activity.
RNA leader
sequences are found upstream of the first gene of in
amino acid biosynthetic operons. These RNA elements
form one of two possible structures in regions encoding
very short peptide sequences that are rich in the end product amino
acid of the operon. A terminator structure forms when there is an
excess of the regulatory amino acid and ribosome movement over the
leader transcript is not impeded. When there is a
deficiency of the charged tRNA of the regulatory amino acid the
ribosome translating the leader peptide stalls and the antiterminator
structure forms. This allows RNA polymerase to transcribe the
operon. Known RNA leaders are Histidine operon leader
,
Leucine operon leader
, Threonine operon leader
and the
Tryptophan operon leader
.
Iron response element
s (IRE) are bound by iron response proteins
(IRP).
The IRE is found in UTRs (Untranslated Regions) of various mRNAs whose products are involved in iron metabolism.
When iron concentration is low, IRPs bind the ferritin mRNA IRE leading to translation repression.
Internal ribosome entry site
s (IRES) are a RNA structure
that allow for translation
initiation in the middle of a mRNA sequence as part of the process of protein synthesis.
s (piRNAs) expressed in
mammal
ian testes and somatic cell
s, they form RNA-protein
complexes with Piwi
proteins. These piRNA complexes (piRCs) have
been linked to transcriptional gene silencing of retrotransposon
s
and other genetic elements in germ line cells, particularly those
in spermatogenesis
.
Clustered Regularly Interspaced Short Palindromic Repeats
(CRISPR) are repeats found in the DNA
of many bacteria
and
archaea
. The repeats are separated by spacers of similar length. It has been
demonstrated that these spacers can be derived from phage and
subsequently help protect the cell from infection.
is an RNP enzyme
that adds specific DNA
sequence repeats ("TTAGGG" in vertebrates) to telomeric
regions, which are found at the ends of eukaryotic
chromosomes. The telomeres contain condensed DNA material, giving
stability to the chromosomes. The enzyme is a reverse transcriptase
that carries Telomerase RNA, which is used as a template when it elongates telomeres, which are shortened after each replication cycle
.
Xist (X-inactive-specific transcript) is an long ncRNA gene on the X chromosome
of the placental mammals
that acts as major effector of
the X chromosome inactivation process forming Barr bodies
.
An antisense RNA, Tsix, is a negative regulator of
Xist. X chromosomes lacking Tsix expression (and thus having high levels of Xist transcription)
are inactivated more frequently than normal chromosomes.
In drosophilids
, which also use an XY sex-determination system
, the roX
(RNA on the X) RNAs are involved in dosage compensation.
Both Xist and roX operate by epigenetic
regulation of
transcription through the recruitment of histone-modifying enzymes
.
these are also known as dual function RNAs.
The majority of the known bifunctional RNAs are both mRNAs that encode a
protein and ncRNAs. However there are also a growing number of ncRNAs
that fall into two different ncRNA categories e.g. H/ACA box snoRNA
and miRNA
.
Two well known examples of bifunctional RNAs are SgrS RNA
and RNAIII
. However, a handful of other bifunctional RNAs are known to exist, e.g. SRA (Steroid Receptor Activator)
,
VegT RNA
,
Oskar RNA
and ENOD40
.
As with protein
s, mutations or imbalances in the ncRNA repertoire within the body can cause a variety of diseases.
ous tissues. These include miRNAs,
long mRNA-like ncRNAs
,
GAS5
,
SNORD50
,
telomerase RNA and Y RNA
s.
The miRNAs are involved in the large scale regulation of many protein coding genes, the Y RNAs are important for the initiation of DNA replication, telomerase RNA that serves as a primer for telomerase, an RNP that extends telomeric regions
at chromosome ends (see telomeres and disease for more information). The direct function of the long mRNA-like ncRNAs is less clear.
Germ-line mutations in miR-16-1
and miR-15
primary precursors have been shown to be much more frequent in patients with chronic lymphocytic leukemia
compared to control populations.
It has been suggested that a rare SNP (rs11614913) that overlaps hsa-mir-196a2
has been found to be associated with non-small cell lung carcinoma. Likewise, a screen of 17 miRNAs that have been predicted to regulate a number of breast cancer associated genes found variations in the microRNAs
miR-17
and miR-30c-1
, these patients were noncarriers of BRCA1
or BRCA2
mutations, lending the possibility that familial breast cancer may be caused by variation in these miRNAs.
The p53
tumor suppressor is arguably the most important player in preventing tumor formation and progression. The p53 protein functions as a transcription factor with a crucial role in orchestrating the cellular stress response. In addition to its crucial role in cancer, p53 has been implicated in other diseases including diabetes, cell death after ischemia, and various neurodegenerative diseases such as Huntington, Parkinson, and Alzheimer. Studies have suggested that p53 expression is subject to regulation by non-coding RNA.
has been shown to be the primary cause of Prader–Willi syndrome. Prader–Willi is a developmental disorder associated with over-eating and learning difficulties. SNORD116 has potential target sites within a number of protein-coding genes, and could have a role in regulating alternative splicing.
gene cluster has been duplicated in approximately 5% of individuals with autistic traits
.
A mouse model engineered to have a duplication of the SNORD115 cluster displays autistic-like behaviour.
have been shown to cause cartilage-hair hypoplasia
, a disease associated with an array of symptoms such as short stature, sparse hair, skeletal abnormalities and a suppressed immune system that is frequent among Amish
and Finnish
. The best characterised variant is an A-to-G transition
at nucleotide 70 that is in a loop region two bases 5' of a conserved
pseudoknot
. However, many other mutations within RNase MRP also cause CHH.
is transcribed from the opposite strand to BACE1 and is upregulated in patients with Alzheimer's disease
. BACE1-AS regulates the expression of BACE1 by increasing BACE1 mRNA stability and generating additional BACE1 through a post-transcriptional feed-forward mechanism. By the same mechanism it also raises concentrations of beta amyloid, the main constituent of senile plaques. BACE1-AS concentrations are elevated in subjects with Alzheimer's disease and in amyloid precursor protein transgenic mice.
has been associated with autosomal dominant, progressive hearing loss in humans and mice. The homozygous mutant mice were profoundly deaf, showing no cochlear
responses. Heterozygous mice and humans progressively lose the ability to hear.
have started using the term functional RNA (fRNA), as opposed to ncRNA, to describe regions functional at the RNA level that may or may not be stand-alone RNA transcripts.
Therefore, every ncRNA is a fRNA, but there exist fRNA (such as riboswitches, SECIS elements, and other cis-regulatory regions) that are not ncRNA. Yet the term fRNA could also include mRNA
as this is RNA coding for protein and hence is functional. Additionally artificially evolved RNAs
also fall under the fRNA umbrella term.
Some publications state that the terms ncRNA and fRNA are nearly synonymous.
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
molecule that is not translated
Translation (genetics)
In molecular biology and genetics, translation is the third stage of protein biosynthesis . In translation, messenger RNA produced by transcription is decoded by the ribosome to produce a specific amino acid chain, or polypeptide, that will later fold into an active protein...
into a 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...
. Less-frequently used synonyms are non-protein-coding RNA (npcRNA), non-messenger RNA (nmRNA) and functional RNA (fRNA). The term small RNA (sRNA) is often used for short bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
l ncRNAs. The DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
sequence from which a non-coding RNA is transcribed is often called an RNA 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...
.
Non-coding RNA genes include highly abundant and functionally important RNAs such as transfer RNA
Transfer RNA
Transfer RNA is an adaptor molecule composed of RNA, typically 73 to 93 nucleotides in length, that is used in biology to bridge the three-letter genetic code in messenger RNA with the twenty-letter code of amino acids in proteins. The role of tRNA as an adaptor is best understood by...
(tRNA) 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...
(rRNA), as well as RNAs such as snoRNA
SnoRNA
Small nucleolar RNAs are a class of small RNA molecules that primarily guide chemical modifications of other RNAs, mainly ribosomal RNAs, transfer RNAs and small nuclear RNAs...
s, microRNAs, siRNA
Sírna
Sírna Sáeglach , son of Dian mac Demal, son of Demal mac Rothechtaid, son of Rothechtaid mac Main, was, according to medieval Irish legend and historical tradition, a High King of Ireland...
s and piRNA
Pirna
Pirna is a town in the Free State of Saxony, Germany, capital of the administrative district Sächsische Schweiz-Osterzgebirge. The town's population is over 40,000. Pirna is located near Dresden and is an important district town as well as a Große Kreisstadt...
s and the long ncRNA
Long noncoding RNA
Long non-coding RNAs are generally considered as non-protein coding transcripts longer than 200 nucleotides. This limit is due to practical considerations including the separation of RNAs in common experimental protocols...
s that include examples such as Xist and HOTAIR
HOTAIR
HOTAIR is a gene at size 6,232 bp encoding 2.2 kbp long noncoding RNA molecule, which controls gene expression on chromosome 2. Its source DNA is located within a HOXC gene cluster. It is the first example of an RNA expressed on one chromosome influencing transcription on another chromosome...
(see here for a more complete list of ncRNAs). The number of ncRNAs encoded within the human genome is unknown, however recent transcriptomic and bioinformatic studies suggest the existence of thousands of ncRNAs., but see Since many of the newly identified ncRNAs have not been validated for their function, it is possible that many are non-functional.
History and discovery
Nucleic acidNucleic 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...
s were first discovered in 1868 by Friedrich Miescher
Friedrich Miescher
Johannes Friedrich Miescher was a Swiss physician and biologist. He was the first researcher to isolate and identify nucleic acid.-Biography:...
and by 1939 RNA had been implicated in protein synthesis
Protein biosynthesis
Protein biosynthesis is the process in which cells build or manufacture proteins. The term is sometimes used to refer only to protein translation but more often it refers to a multi-step process, beginning with amino acid synthesis and transcription of nuclear DNA into messenger RNA, which is then...
. Two decades later, Francis Crick
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...
predicted a functional RNA component which mediated translation
Translation (genetics)
In molecular biology and genetics, translation is the third stage of protein biosynthesis . In translation, messenger RNA produced by transcription is decoded by the ribosome to produce a specific amino acid chain, or polypeptide, that will later fold into an active protein...
; he reasoned that RNA is better suited to base-pair with an mRNA transcript than a pure polypeptide.
The first non-coding RNA to be characterised was an alanine
Alanine
Alanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
tRNA found in baker's yeast
Baker's yeast
Baker's yeast is the common name for the strains of yeast commonly used as a leavening agent in baking bread and bakery products, where it converts the fermentable sugars present in the dough into carbon dioxide and ethanol...
, its structure was published in 1965. To produce a purified alanine tRNA sample, Robert W. Holley
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...
et al. used 140kg
Kilogram
The kilogram or kilogramme , also known as the kilo, is the base unit of mass in the International System of Units and is defined as being equal to the mass of the International Prototype Kilogram , which is almost exactly equal to the mass of one liter of water...
of commercial baker's yeast to give just 1g
Gram
The gram is a metric system unit of mass....
of purified tRNAAla for analysis. The 80 nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
tRNA was sequenced by first being digested with Pancreatic ribonuclease
Pancreatic ribonuclease
Pancreatic ribonucleasea are pyrimidine-specific endonucleases found in high quantity in the pancreas of certain mammals and of some reptiles....
(producing fragments ending in Cytosine
Cytosine
Cytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
or Uridine
Uridine
Uridine is a molecule that is formed when uracil is attached to a ribose ring via a β-N1-glycosidic bond.If uracil is attached to a deoxyribose ring, it is known as a deoxyuridine....
) and then with takadiastase ribonuclease Tl (producing fragments which finished with Guanosine
Guanosine
Guanosine is a purine nucleoside comprising guanine attached to a ribose ring via a β-N9-glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate , cyclic guanosine monophosphate , guanosine diphosphate , and guanosine triphosphate...
). Chromatography
Chromatography
Chromatography is the collective term for a set of laboratory techniques for the separation of mixtures....
and identification of the 5' and 3' ends then helped arrange the fragments to establish the RNA sequence. Of the three structures originally proposed for this tRNA, the 'cloverleaf' structure was independently proposed in several following publications. The cloverleaf secondary structure
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
was finalised following 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...
anaylsis performed by two independent research groups in 1974.
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...
was next to be discovered, followed by URNA in the early 1980s. Since then, the discovery of new non-coding RNAs has continued with snoRNAs, Xist, CRISPR
CRISPR
CRISPRs are loci containing multiple short direct repeats that are found in the genomes of approximately 40% of bacteria and 90% of archaea. CRISPR functions as a prokaryotic immune system, in that it confers resistance to exogenous genetic elements such as plasmids and phages...
and many more. Recent notable additions include riboswitch
Riboswitch
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 and miRNA
Mirna
Mirna may refer to:geographical entities* Mirna , a river in Istria, Croatia* Mirna , a river in Slovenia, tributary of the river Sava* Mirna , a settlement in the municipality of Mirna in Southeastern Sloveniapeople...
, the discovery of the RNAi mechanism
Mechanism
Mechanism may refer to:*Mechanism , rigid bodies connected by joints in order to accomplish a desired force and/or motion transmission*Mechanism , explaining how a feature is created...
associated with the latter earned Craig C. Mello and Andrew Fire
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...
the 2006 Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
.
Biological roles of ncRNA
Noncoding RNAs belong to several groups and are involved in many cellularprocesses. These range from ncRNAs of central importance that are
conserved across all or most cellular life through to more transient
ncRNAs specific to one or a few closely related species. The more
conserved ncRNAs are thought to be molecular fossils or relics from
LUCA
Luca
Luca is Italian and Romanian for the name Luke.Luca or LUCA may refer to: the Last Universal Common Ancestor.*Luca is the greek word for legendary- People :* Luca , including a list of people with the given name Luca...
and the RNA world
RNA 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...
.
ncRNAs in translation
Translation (genetics)
In molecular biology and genetics, translation is the third stage of protein biosynthesis . In translation, messenger RNA produced by transcription is decoded by the ribosome to produce a specific amino acid chain, or polypeptide, that will later fold into an active protein...
. 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...
(RNP) particles called 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....
s are the 'factories' where translation takes place in the cell. The ribosome consists of more than 60% ribosomal RNA, these are made up of 3 ncRNAs in prokaryotes and 4 ncRNAs in eukaryotes. Ribosomal RNAs catalyse the translation of nucleotide sequences to protein. Another set of ncRNAs, Transfer RNA
Transfer RNA
Transfer RNA is an adaptor molecule composed of RNA, typically 73 to 93 nucleotides in length, that is used in biology to bridge the three-letter genetic code in messenger RNA with the twenty-letter code of amino acids in proteins. The role of tRNA as an adaptor is best understood by...
s, form an 'adaptor molecule' between mRNA and protein. The H/ACA box and C/D box snoRNAs
SnoRNA
Small nucleolar RNAs are a class of small RNA molecules that primarily guide chemical modifications of other RNAs, mainly ribosomal RNAs, transfer RNAs and small nuclear RNAs...
are ncRNAs found in archaea and eukaryotes, RNase MRP
RNase MRP
RNase MRP is an enzymatically active ribonucleoprotein with two distinct roles in eukaryotes. In mitochondria it plays a direct role in the initiation of mitochondrial DNA replication. In the nucleus it is involved in precursor rRNA processing, where it cleaves the internal transcribed spacer 1...
is restricted to eukaryotes, both groups of ncRNA are involved in the maturation of rRNA. The snoRNAs guide covalent modifications of rRNA, tRNA and snRNAs, RNase MRP cleaves the internal transcribed spacer 1 between 18S and 5.8S rRNAs. The ubiquitous ncRNA, RNase P
RNase P
Ribonuclease P is a type of ribonuclease which cleaves RNA. RNase P is unique from other RNases in that it is a ribozyme – a ribonucleic acid that acts as a catalyst in the same way that a protein based enzyme would. Its function is to cleave off an extra, or precursor, sequence of RNA on tRNA...
, is an evolutionary relative of RNase MRP. RNase P matures tRNA sequences by generating mature 5'-ends of tRNAs through cleaving the 5'-leader elements of precursor-tRNAs. Another ubiquitous RNP called SRP
Signal recognition particle
The signal recognition particle is an abundant, cytosolic, universally conserved ribonucleoprotein that recognizes and targets specific proteins to the endoplasmic reticulum in eukaryotes and the plasma membrane in prokaryotes....
recognizes and transports specific nascent proteins to the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
in eukaryote
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
s and the plasma membrane in prokaryote
Prokaryote
The prokaryotes are a group of organisms that lack a cell nucleus , or any other membrane-bound organelles. The organisms that have a cell nucleus are called eukaryotes. Most prokaryotes are unicellular, but a few such as myxobacteria have multicellular stages in their life cycles...
s. In bacteria Transfer-messenger RNA
TmRNA
Transfer-messenger RNA is a bacterial RNA molecule with dual tRNA-like and messenger RNA-like properties. The tmRNA forms a ribonucleoprotein complex together with Small Protein B , Elongation Factor Tu , and ribosomal protein S1...
(tmRNA) is an RNP involved in rescuing stalled ribosomes, tagging incomplete polypeptides
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
and promoting the degradation of aberrant mRNA.
ncRNAs in RNA splicing
Spliceosome
A spliceosome is a complex of snRNA and protein subunits that removes introns from a transcribed pre-mRNA segment. This process is generally referred to as splicing.-Composition:...
performs the 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 essential
for removing intron
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
sequences, this process is required for the formation of mature mRNA.
The spliceosome
Spliceosome
A spliceosome is a complex of snRNA and protein subunits that removes introns from a transcribed pre-mRNA segment. This process is generally referred to as splicing.-Composition:...
is another RNP often also known as the snRNP
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...
or tri-snRNP.
There are two different forms of the spliceosome, the major and minor forms.
The ncRNA components of the major spliceosome are U1, U2,
U4, U5, and U6.
The ncRNA components of the minor spliceosome are U11, U12,
U5, U4atac
U4atac minor spliceosomal RNA
U4atac minor spliceosomal RNA is a ncRNA which is an essential component of the minor U12-type spliceosome complex. The U12-type spliceosome is required for removal of the rarer class of eukaryotic introns ....
and
U6atac
U6atac minor spliceosomal RNA
U6atac minor spliceosomal RNA is a non-coding RNA which is an essential component of the minor U12-type spliceosome complex. The U12-type spliceosome is required for removal of the rarer class of eukaryotic introns ....
.
Another group of introns can catalyse their own removal from host transcripts, these are called self-splicing RNAs.
There are two main groups of self-splicing RNAs, these are the group I catalytic intron
Group I catalytic intron
Group I introns are large self-splicing ribozymes. They catalyze their own excision from mRNA, tRNA and rRNA precursors in a wide range of organisms. The core secondary structure consists of nine paired regions...
and
group II catalytic intron. These ncRNAs catalyze their own excision from mRNA, tRNA and rRNA precursors in a wide range of organisms.
In mammals it has been found that snoRNAs can also regulate the alternative splicing
Alternative 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...
of
mRNA, for example snoRNA HBII-52
Small nucleolar RNA SNORD115
SNORD115 is a non-coding RNA molecule known as a small nucleoloar RNA which usually functions in guiding the modification of other non-coding RNAs. This type of modifiying RNA is usually located in the nucleolus of the eukaryotic cell which is a major site of snRNA biogenesis...
regulates the splicing of
serotonin receptor 2C
5-HT2C receptor
The 5-HT2C receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gq/G11 and mediates excitatory neurotransmission. HTR2C denotes the human gene encoding for the receptor, that in humans is located at the...
.
In nematodes the SmY ncRNA appears to be involved in mRNA trans-splicing
Trans-splicing
Trans-splicing is a special form of RNA processing in eukaryotes where exons from two different primary RNA transcripts are joined end to end and ligated....
.
ncRNAs in gene regulation
The expressionGene 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...
of many thousands of 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...
s are regulated by ncRNAs.
This regulation can occur in trans
Trans-acting
In the field of molecular biology, trans-acting , in general, means "acting from a different molecule"...
or in cis.
trans-acting ncRNAs
In higher eukaryotes microRNAs regulate gene expression. A single miRNAcan reduce the expression levels of hundreds of genes. The mechanism by which mature miRNA molecules
act is through partial complementary to one or more messenger RNA (mRNA) molecules, generally in
3' UTRs
Three prime untranslated region
In molecular genetics, the three prime untranslated region is a particular section of messenger RNA . It is preceeded by the coding region....
. The main function of miRNAs is to down-regulate
gene expression.
The ncRNA RNase P
RNase P
Ribonuclease P is a type of ribonuclease which cleaves RNA. RNase P is unique from other RNases in that it is a ribozyme – a ribonucleic acid that acts as a catalyst in the same way that a protein based enzyme would. Its function is to cleave off an extra, or precursor, sequence of RNA on tRNA...
has also been shown to influence gene expression.
In the human nucleus RNase P
RNase P
Ribonuclease P is a type of ribonuclease which cleaves RNA. RNase P is unique from other RNases in that it is a ribozyme – a ribonucleic acid that acts as a catalyst in the same way that a protein based enzyme would. Its function is to cleave off an extra, or precursor, sequence of RNA on tRNA...
is required for the
normal and efficient transcription of various ncRNAs transcribed by
RNA polymerase III
RNA polymerase III
RNA polymerase III transcribes DNA to synthesize ribosomal 5S rRNA, tRNA and other small RNAs. The genes transcribed by RNA Pol III fall in the category of "housekeeping" genes whose expression is required in all cell types and most environmental conditions...
. These include tRNA, 5S rRNA
5S ribosomal RNA
5S ribosomal RNA is a component of the large ribosomal subunit in both prokaryotes and eukaryotes .Eukaryotic 5S rRNA is synthesised by RNA polymerase III, whereas most other eukaroytic rRNAs are cleaved from a 45S precursor transcribed by RNA polymerase I...
,
SRP
Signal recognition particle
The signal recognition particle is an abundant, cytosolic, universally conserved ribonucleoprotein that recognizes and targets specific proteins to the endoplasmic reticulum in eukaryotes and the plasma membrane in prokaryotes....
RNA and U6 snRNA
U6 spliceosomal RNA
U6 snRNA is the non-coding small nuclear RNA component of U6 snRNP , an RNA-protein complex that combines with other snRNPs, unmodified pre-mRNA, and various other proteins to assemble a spliceosome, a large RNA-protein molecular complex upon which splicing of pre-mRNA occurs...
genes. RNase P exerts its role in transcription through association with
Pol III and chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
of active tRNA and 5S rRNA genes.
It has been shown that 7SK RNA
7SK RNA
-External links:...
, a metazoan ncRNA, acts as a negative regulator of the
RNA polymerase II
RNA polymerase II
RNA polymerase II is an enzyme found in eukaryotic cells. It catalyzes the transcription of DNA to synthesize precursors of mRNA and most snRNA and microRNA. A 550 kDa complex of 12 subunits, RNAP II is the most studied type of RNA polymerase...
elongation factor P-TEFb
Elongation factor
Elongation factors are a set of proteins that facilitate the events of translational elongation, the steps in protein synthesis from the formation of the first peptide bond to the formation of the last one.Elongation is the most rapid step in translation:...
, and that this activity is
influenced by stress response pathways.
The bacterial ncRNA, 6S RNA, specifically associates with RNA polymerase holoenzyme
containing the sigma70
Sigma factor
A sigma factor is a bacterial transcription initiation factor that enables specific binding of RNA polymerase to gene promoters. Different sigma factors are activated in response to different environmental conditions...
specificity factor. This interaction represses
expression from a sigma70-dependent promoter during stationary phase
Bacterial growth
250px|right|thumb|Growth is shown as L = log where numbers is the number of colony forming units per ml, versus T Bacterial growth is the division of one bacterium into two daughter cells in a process called binary fission. Providing no mutational event occurs the resulting daughter cells are...
.
Another bacterial ncRNA, OxyS RNA
OxyS RNA
OxyS RNA is a small non-coding RNA which is induced in response to oxidative stress in Escherichia coli. This RNA acts as a global regulator to activate or repress the expression of as many as 40 genes, by an antisense mechanism, including the fhlA-encoded transcriptional activator and the...
represses translation by binding to Shine-Dalgarno sequences thereby occluding ribosome binding. OxyS RNA is induced in response to oxidative stress in Escherichia coli.
The B2 RNA is a small noncoding RNA polymerase III transcript that represses mRNA transcription in response to heat shock in mouse
cells. B2 RNA inhibits transcription by binding to core Pol II. Through this interaction, B2 RNA assembles into preinitiation
complexes at the promoter and blocks RNA synthesis.
A recent study has shown that just the act of transcription of ncRNA
sequence can have an influence on gene expression. RNA polymerase II
RNA polymerase II
RNA polymerase II is an enzyme found in eukaryotic cells. It catalyzes the transcription of DNA to synthesize precursors of mRNA and most snRNA and microRNA. A 550 kDa complex of 12 subunits, RNAP II is the most studied type of RNA polymerase...
transcription of ncRNAs is required for chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
remodelling
in the Schizosaccharomyces pombe
Schizosaccharomyces pombe
Schizosaccharomyces pombe, also called "fission yeast", is a species of yeast. It is used as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically measure 3 to 4 micrometres in diameter and 7 to 14 micrometres in length...
. Chromatin is progressively
converted to an open configuration, as several species of ncRNAs are
transcribed.
cis-acting ncRNAs
A number of ncRNAs are embedded in the 5' UTRs of protein coding genesand influence their expression in various ways. For
example, a riboswitch
Riboswitch
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...
can directly
bind a small target molecule
Small molecule
In the fields of pharmacology and biochemistry, a small molecule is a low molecular weight organic compound which is by definition not a polymer...
, the binding of the target affects
the gene's activity.
RNA leader
Attenuator (genetics)
Attenuation is a regulatory feature found throughout Archaea and Bacteria causing premature termination of transcription. Attenuators are 5'-cis acting regulatory regions which fold into one of two alternative RNA structures which determine the success of transcription...
sequences are found upstream of the first gene of in
amino acid biosynthetic operons. These RNA elements
Cis-regulatory element
A cis-regulatory element or cis-element is a region of DNA or RNA that regulates the expression of genes located on that same molecule of DNA . This term is constructed from the Latin word cis, which means "on the same side as". These cis-regulatory elements are often binding sites for one or...
form one of two possible structures in regions encoding
very short peptide sequences that are rich in the end product amino
acid of the operon. A terminator structure forms when there is an
excess of the regulatory amino acid and ribosome movement over the
leader transcript is not impeded. When there is a
deficiency of the charged tRNA of the regulatory amino acid the
ribosome translating the leader peptide stalls and the antiterminator
structure forms. This allows RNA polymerase to transcribe the
operon. Known RNA leaders are Histidine operon leader
Histidine operon leader
The Histidine operon leader is an RNA element found in the bacterial histidine operon. At least 6 amino acid operons are known to be regulated by attenuation. In each a leader sequence of 150-200 bp is found upstream of the first gene in the operon. This leader sequence can assume two different...
,
Leucine operon leader
Leucine operon leader
The Leucine operon leader is an RNA element found upstream of the first gene in the Leucine biosynthetic operon. The leader sequence can assume two different secondary structures known as the terminator and the anti-terminator structure. The leader also codes for very short peptide sequence that is...
, Threonine operon leader
Threonine operon leader
The threonine operon leader is an RNA element. Threonine is one of at least 6 amino acid operons are known to be regulated by attenuation. In each a leader sequence of 150-200 bp is found upstream of the first gene in the operon. This leader sequence can assume two different secondary structures...
and the
Tryptophan operon leader
Tryptophan operon leader
The Tryptophan operon leader is an RNA element found at the 5' of some bacterial tryptophan operons. The leader sequence can assume two different secondary structures known as the terminator and the anti-terminator structure. The leader also codes for very short peptide sequence that is rich in...
.
Iron response element
Iron response element
The Iron response element or Iron-responsive element is a short conserved stem-loop which is bound by iron response proteins . The IRE is found in UTRs of various mRNAs whose products are involved in iron metabolism. For example, the mRNA of ferritin contains one IRE in its 5' UTR...
s (IRE) are bound by iron response proteins
Iron-responsive element binding protein
The iron-responsive element-binding proteins, also known as IRE-BP and IRBP and IRP, bind to iron-responsive elements in the regulation of human iron metabolism.-Function:...
(IRP).
The IRE is found in UTRs (Untranslated Regions) of various mRNAs whose products are involved in iron metabolism.
When iron concentration is low, IRPs bind the ferritin mRNA IRE leading to translation repression.
Internal ribosome entry site
Internal ribosome entry site
An internal ribosome entry site, abbreviated IRES, is a nucleotide sequence that allows for translation initiation in the middle of a messenger RNA sequence as part of the greater process of protein synthesis...
s (IRES) are a RNA structure
RNA structure
Biomolecular structure is the structure of biomolecules, mainly proteins and the nucleic acids DNA and RNA. The structure of these molecules is frequently decomposed into primary structure, secondary structure, tertiary structure, and quaternary structure. The scaffold for this structure is...
that allow for translation
Translation (genetics)
In molecular biology and genetics, translation is the third stage of protein biosynthesis . In translation, messenger RNA produced by transcription is decoded by the ribosome to produce a specific amino acid chain, or polypeptide, that will later fold into an active protein...
initiation in the middle of a mRNA sequence as part of the process of protein synthesis.
ncRNAs and genome defense
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) expressed in
mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
ian testes and somatic cell
Somatic cell
A somatic cell is any biological cell forming the body of an organism; that is, in a multicellular organism, any cell other than a gamete, germ cell, gametocyte or undifferentiated stem cell...
s, they form RNA-protein
complexes with Piwi
Piwi
The piwi class of genes was originally identified as encoding regulatory proteins responsible for maintaining incomplete differentiation in stem cells and maintaining the stability of cell division rates in germ line cells...
proteins. These piRNA complexes (piRCs) have
been linked to transcriptional gene silencing of retrotransposon
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...
s
and other genetic elements in germ line cells, particularly those
in spermatogenesis
Spermatogenesis
Spermatogenesis is the process by which male primary germ cells undergo division, and produce a number of cells termed spermatogonia, from which the primary spermatocytes are derived. Each primary spermatocyte divides into two secondary spermatocytes, and each secondary spermatocyte into two...
.
Clustered Regularly Interspaced Short Palindromic Repeats
CRISPR
CRISPRs are loci containing multiple short direct repeats that are found in the genomes of approximately 40% of bacteria and 90% of archaea. CRISPR functions as a prokaryotic immune system, in that it confers resistance to exogenous genetic elements such as plasmids and phages...
(CRISPR) are repeats found in the DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
of many bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
and
archaea
Archaea
The Archaea are a group of single-celled microorganisms. A single individual or species from this domain is called an archaeon...
. The repeats are separated by spacers of similar length. It has been
demonstrated that these spacers can be derived from phage and
subsequently help protect the cell from infection.
ncRNAs and chromosome structure
TelomeraseTelomerase
Telomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from...
is an RNP enzyme
Enzyme
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...
that adds specific DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
sequence repeats ("TTAGGG" in vertebrates) to telomeric
Telomere
A telomere is a region of repetitive DNA sequences at the end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos "end" and merοs "part"...
regions, which are found at the ends of eukaryotic
chromosomes. The telomeres contain condensed DNA material, giving
stability to the chromosomes. The enzyme is a 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...
that carries Telomerase RNA, which is used as a template when it elongates telomeres, which are shortened after each replication cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
.
Xist (X-inactive-specific transcript) is an long ncRNA gene on the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
of the placental mammals
Eutheria
Eutheria is a group of mammals consisting of placental mammals plus all extinct mammals that are more closely related to living placentals than to living marsupials . They are distinguished from noneutherians by various features of the feet, ankles, jaws and teeth...
that acts as major effector of
the X chromosome inactivation process forming Barr bodies
Barr body
A Barr body is the inactive X chromosome in a female somatic cell, rendered inactive in a process called lyonization, in those species in which sex is determined by the presence of the Y or W chromosome rather than the diploidy of the X or Z...
.
An antisense RNA, Tsix, is a negative regulator of
Xist. X chromosomes lacking Tsix expression (and thus having high levels of Xist transcription)
are inactivated more frequently than normal chromosomes.
In drosophilids
Drosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
, which also use an XY sex-determination system
XY sex-determination system
The XY sex-determination system is the sex-determination system found in humans, most other mammals, some insects and some plants . In this system, females have two of the same kind of sex chromosome , and are called the homogametic sex. Males have two distinct sex chromosomes , and are called...
, the roX
Drosophila roX RNA
RoX RNA is a non-coding RNA present in the male-specific lethal complex and is required for sex dosage compensation in Drosophila. As males only contain one X chromosome, male flies dosage compensate for the X chromosome by hyper-transcribing the X chromosome...
(RNA on the X) RNAs are involved in dosage compensation.
Both Xist and roX operate by epigenetic
Epigenetics
In biology, and specifically genetics, epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence – hence the name epi- -genetics...
regulation of
transcription through the recruitment of histone-modifying enzymes
Histone-Modifying Enzymes
The packaging of the eukaryotic genome into highly condensed chromatin makes it inaccessible to the factors required for gene transcription, DNA replication, recombination and repair. Eukaryotes have developed intricate mechanisms to overcome this repressive barrier imposed by the chromatin...
.
Bifunctional RNA
Bifunctional RNAs are RNAs that have two distinct functions,these are also known as dual function RNAs.
The majority of the known bifunctional RNAs are both mRNAs that encode a
protein and ncRNAs. However there are also a growing number of ncRNAs
that fall into two different ncRNA categories e.g. H/ACA box snoRNA
SnoRNA
Small nucleolar RNAs are a class of small RNA molecules that primarily guide chemical modifications of other RNAs, mainly ribosomal RNAs, transfer RNAs and small nuclear RNAs...
and miRNA
Mirna
Mirna may refer to:geographical entities* Mirna , a river in Istria, Croatia* Mirna , a river in Slovenia, tributary of the river Sava* Mirna , a settlement in the municipality of Mirna in Southeastern Sloveniapeople...
.
Two well known examples of bifunctional RNAs are SgrS RNA
SgrS RNA
SgrS is a 227 nucleotide small RNA that is activated by SgrR in Escherichia coli during glucose-phosphate stress. The nature of glucose-phosphate stress is not fully understood, but is correlated with intracellular accumulation of glucose-6-phosphate...
and RNAIII
RNAIII
RNAIII is a small RNA which is known to regulate the expression of many Staphylococcus aureus genes encoding exoproteins and cell wall associated proteins. In S. aureus, RNAIII acts as the effector of the agr quorum sensing system and is transcribed from the P3 operon. The RNAIII transcript also...
. However, a handful of other bifunctional RNAs are known to exist, e.g. SRA (Steroid Receptor Activator)
,
VegT RNA
,
Oskar RNA
and ENOD40
ENOD40
enod40, also known as early nodulin 40, is a gene found in flowering plants. The gene has characteristics of both protein and Non-coding RNA genes...
.
ncRNAs and disease
See also: Long noncoding RNAs in diseaseAs with 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, mutations or imbalances in the ncRNA repertoire within the body can cause a variety of diseases.
Cancer
Many ncRNAs show abnormal expression patterns in cancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
ous tissues. These include miRNAs,
long mRNA-like ncRNAs
,
GAS5
GAS5
Growth arrest-specific 5 is a non-protein coding RNA that in humans is encoded by the GAS5 gene.GAS5 noncoding RNA, which accumulates in growth arrested cells, acts as a decoy hormone response element for the glucocorticoid receptor and hence blocks the upregulation of gene expression by activated...
,
SNORD50
Small nucleolar RNA SNORD50
snoRNA U50 is a non-coding RNA molecule which functions in the modification of other small nuclear RNAs . This type of modifiying RNA is usually located in the nucleolus of the eukaryotic cell which is a major site of snRNA biogenesis...
,
telomerase RNA and Y RNA
Y RNA
Y RNAs are small non-coding RNA components of the Ro ribonucleoprotein particle . The Ro RNP was first identified by Lerner et al.. as a target of autoimmune antibodies in patients with systemic lupus erythematosus.-Function:...
s.
The miRNAs are involved in the large scale regulation of many protein coding genes, the Y RNAs are important for the initiation of DNA replication, telomerase RNA that serves as a primer for telomerase, an RNP that extends telomeric regions
Telomere
A telomere is a region of repetitive DNA sequences at the end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos "end" and merοs "part"...
at chromosome ends (see telomeres and disease for more information). The direct function of the long mRNA-like ncRNAs is less clear.
Germ-line mutations in miR-16-1
Mir-16 microRNA precursor family
The miR-16 microRNA precursor family is a group of related small non-coding RNA genes that regulates gene expression. miR-16, miR-15, mir-195 and miR-457 are related microRNA precursor sequences from the mir-15 gene family...
and miR-15
Mir-15 microRNA precursor family
The miR-15 microRNA precursor family are small non-coding RNA genes that regulate gene expression. The family includes the related mir-15a and mir-15b sequences. In humans miR-15a and miR-16 are clustered within 0.5 kilobases at 13q14. This region has been shown to be deleted in more than half of...
primary precursors have been shown to be much more frequent in patients with chronic lymphocytic leukemia
Chronic lymphocytic leukemia
B-cell chronic lymphocytic leukemia , also known as chronic lymphoid leukemia , is the most common type of leukemia. Leukemias are cancers of the white blood cells . CLL affects B cell lymphocytes. B cells originate in the bone marrow, develop in the lymph nodes, and normally fight infection by...
compared to control populations.
It has been suggested that a rare SNP (rs11614913) that overlaps hsa-mir-196a2
Mir-196 microRNA precursor family
miR-196 is a non-coding RNA called a microRNA that has been shown to be expressed in human and mouse [1,2]. miR-196 appears to be a vertebrate specific microRNA and has now been predicted or experimentally confirmed in a wide range of vertebrate species . In many species the miRNA appears to be...
has been found to be associated with non-small cell lung carcinoma. Likewise, a screen of 17 miRNAs that have been predicted to regulate a number of breast cancer associated genes found variations in the microRNAs
miR-17
Mir-17 microRNA precursor family
The miR-17 microRNA precursor family are a group of related small non-coding RNA genes called microRNAs that regulate gene expression. The microRNA precursor miR-17 family, includes miR-20, miR-91, and miR-103. miRNAs are transcribed as ~70 nucleotide precursors and subsequently processed by the...
and miR-30c-1
Mir-30 microRNA precursor
miR-30 microRNA precursor is a small non-coding RNA that regulates gene expression. Animal microRNAs are transcribed as ~70 nucleotide stem-loop precursor and subsequently processed by the Dicer enzyme to give a mature ~22 nucleotide product. In this case the mature sequence comes from both the 3' ...
, these patients were noncarriers of BRCA1
BRCA1
BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
or BRCA2
BRCA2
BRCA2 is a protein that in humans is encoded by the BRCA2 gene.BRCA2 orthologs have been identified in most mammals for which complete genome data are available....
mutations, lending the possibility that familial breast cancer may be caused by variation in these miRNAs.
The p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
tumor suppressor is arguably the most important player in preventing tumor formation and progression. The p53 protein functions as a transcription factor with a crucial role in orchestrating the cellular stress response. In addition to its crucial role in cancer, p53 has been implicated in other diseases including diabetes, cell death after ischemia, and various neurodegenerative diseases such as Huntington, Parkinson, and Alzheimer. Studies have suggested that p53 expression is subject to regulation by non-coding RNA.
Prader–Willi syndrome
The deletion of the 48 copies of the C/D box snoRNA SNORD116Small nucleolar RNA SNORD116
SNORD116 is a non-coding RNA molecule which functions in the modification of other small nuclear RNAs . This type of modifiying RNA is usually located in the nucleolus of the eukaryotic cell which is a major site of snRNA biogenesis...
has been shown to be the primary cause of Prader–Willi syndrome. Prader–Willi is a developmental disorder associated with over-eating and learning difficulties. SNORD116 has potential target sites within a number of protein-coding genes, and could have a role in regulating alternative splicing.
Autism
The chromosomal locus containing the small nucleolar RNA SNORD115Small nucleolar RNA SNORD115
SNORD115 is a non-coding RNA molecule known as a small nucleoloar RNA which usually functions in guiding the modification of other non-coding RNAs. This type of modifiying RNA is usually located in the nucleolus of the eukaryotic cell which is a major site of snRNA biogenesis...
gene cluster has been duplicated in approximately 5% of individuals with autistic traits
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
.
A mouse model engineered to have a duplication of the SNORD115 cluster displays autistic-like behaviour.
Cartilage-hair hypoplasia
Mutations within RNase MRPRNase MRP
RNase MRP is an enzymatically active ribonucleoprotein with two distinct roles in eukaryotes. In mitochondria it plays a direct role in the initiation of mitochondrial DNA replication. In the nucleus it is involved in precursor rRNA processing, where it cleaves the internal transcribed spacer 1...
have been shown to cause cartilage-hair hypoplasia
Cartilage-hair hypoplasia
Cartilage–hair hypoplasia , also known as McKusick type metaphyseal chondrodysplasia, is a rare form of short-limbed dwarfism due to skeletal dysplasia. It was first reported in 1965 by McKusick et al...
, a disease associated with an array of symptoms such as short stature, sparse hair, skeletal abnormalities and a suppressed immune system that is frequent among Amish
Amish
The Amish , sometimes referred to as Amish Mennonites, are a group of Christian church fellowships that form a subgroup of the Mennonite churches...
and Finnish
Finland
Finland , officially the Republic of Finland, is a Nordic country situated in the Fennoscandian region of Northern Europe. It is bordered by Sweden in the west, Norway in the north and Russia in the east, while Estonia lies to its south across the Gulf of Finland.Around 5.4 million people reside...
. The best characterised variant is an A-to-G transition
Transition (genetics)
In genetics, a transition is a point mutation that changes a purine nucleotide to another purine or a pyrimidine nucleotide to another pyrimidine . Approximately two out of three single nucleotide polymorphisms are transitions....
at nucleotide 70 that is in a loop region two bases 5' of a 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...
pseudoknot
Pseudoknot
A pseudoknot is a nucleic acid secondary structure containing at least two stem-loop structures in which half of one stem is intercalated between the two halves of another stem. The pseudoknot was first recognized in the turnip yellow mosaic virus in 1982...
. However, many other mutations within RNase MRP also cause CHH.
Alzheimer's disease
The antisense RNA, BACE1-ASBACE1-AS
BACE1-AS, also known as BACE1 antisense RNA , is a human gene at 11q23.3 encoding a long noncoding RNA molecule. It is transcribed from the opposite strand to BACE1 and is upregulated in patients with Alzheimer's disease...
is transcribed from the opposite strand to BACE1 and is upregulated in patients with Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
. BACE1-AS regulates the expression of BACE1 by increasing BACE1 mRNA stability and generating additional BACE1 through a post-transcriptional feed-forward mechanism. By the same mechanism it also raises concentrations of beta amyloid, the main constituent of senile plaques. BACE1-AS concentrations are elevated in subjects with Alzheimer's disease and in amyloid precursor protein transgenic mice.
miR-96 and hearing loss
Variation within the seed region of mature miR-96Mir-96 microRNA
miR-96 microRNA precursor is a small non-coding RNA that regulates gene expression. microRNAs are transcribed as ~80 nucleotide precursors and subsequently processed by the Dicer enzyme to give a ~23 nucleotide products. In this case the mature sequence comes from the 5' arm of the precursor.The...
has been associated with autosomal dominant, progressive hearing loss in humans and mice. The homozygous mutant mice were profoundly deaf, showing no cochlear
Cochlear
Cochlear, the adjective form of cochlea, may refer to:* Cochlear implant, a sensory aid for the deaf* Cochlear nuclei, the ventral cochlear nucleus and the dorsal cochlear nucleus...
responses. Heterozygous mice and humans progressively lose the ability to hear.
Distinction between functional RNA (fRNA) and ncRNA
Several publicationshave started using the term functional RNA (fRNA), as opposed to ncRNA, to describe regions functional at the RNA level that may or may not be stand-alone RNA transcripts.
Therefore, every ncRNA is a fRNA, but there exist fRNA (such as riboswitches, SECIS elements, and other cis-regulatory regions) that are not ncRNA. Yet the term fRNA could also include mRNA
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...
as this is RNA coding for protein and hence is functional. Additionally artificially evolved RNAs
Systematic 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....
also fall under the fRNA umbrella term.
Some publications state that the terms ncRNA and fRNA are nearly synonymous.
See also
- List of RNAs
- Nucleic acid structureNucleic acid structureNucleic acid structure refers to the structure of nucleic acids such as DNA and RNA It is often divided into four different levels:* Primary structure—the raw sequence of nucleobases of each of the component DNA strands;...
- RfamRfamRfam is a database containing information about non-coding RNA families and other structured RNA elements. It is an annotated, open access database hosted by the Wellcome Trust Sanger Institute in collaboration with Janelia Farm...
- RiboswitchRiboswitchIn 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...
- RibozymeRibozymeA 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...
- RNAs present in environmental samplesRNAs present in environmental samplesA wide variety of non-coding RNAs have been identified in various species of organisms known to science. However, RNAs have also been identified in "metagenomics" sequences derived from samples of DNA or RNA extracted from the environment, which contain unknown species. Initial work in this area...
External links
- Comprehensive database of mammalian ncRNAs
- The Rfam Database — a curated list of hundreds of families of related ncRNAs.
- NONCODE.org — a free database of all kinds of noncoding RNAs (except tRNAs and rRNAs).
- Joint ncRNA Database — over 30,000 individual sequences from 99 species of bacteria, archaea and eukaryota