Junctional diversity
Encyclopedia
Junctional diversity describes the DNA
sequence variations introduced by the improper joining of gene
segments during the process of V(D)J recombination
. This process of V(D)J recombination has vital roles for the vertebrate
immune system
as it is able to generate a huge repertoire of different T-cell receptor (TCR) and immunoglobulin molecules required for pathogen
antigen
recognition by T-cells and B cells respectively. The inaccuracies of joining provided by junctional diversity is estimated to triple the diversity initially generated by these V(D)J recombinations.
, during which the different variable gene segments (those segments involved in antigen recognition) of TCRs and immunoglobulins are rearranged and unused segments removed. This introduces double-strand breaks between the required segments. These ends form hairpin loops and must be joined together to form a single strand (summarised in diagram, right). This joining is a very inaccurate process which results in the variable addition or subtraction of nucleotide
s and thus generates junctional diversity.
Generation of junctional diversity starts as the proteins, recombination activating gene
-1 and -2 (RAG1 and RAG2), along with DNA repair proteins, such as Artemis
, are responsible for single-stranded cleavage of the hairpin loops and addition of a series of palindromic
, 'P' nucleotides. Subsequently the enzyme, terminal deoxynucleotidyl transferase
(TdT), adds further random ‘N’ nucleotides. The newly synthesised strands anneal to one another, but mismatches are common. Exonuclease
s remove these unpaired nucleotides and the gaps are filled by DNA synthesis
and repair
machinery. Exonucleases may also cause shortening of this junction, however this process is still poorly understood.
Junctional diversity is liable to cause frame-shift mutations and thus production of non-functional proteins. Therefore
there is considerable waste involved in this process.
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 variations introduced by the improper joining 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...
segments during the process of V(D)J recombination
V(D)J recombination
VJ recombination, also known as somatic recombination, is a mechanism of genetic recombination in the early stages of immunoglobulin and T cell receptors production of the immune system...
. This process of V(D)J recombination has vital roles for the vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
as it is able to generate a huge repertoire of different T-cell receptor (TCR) and immunoglobulin molecules required for pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
recognition by T-cells and B cells respectively. The inaccuracies of joining provided by junctional diversity is estimated to triple the diversity initially generated by these V(D)J recombinations.
Process
Junctional diversity concludes the process of somatic recombination or V(D)J recombinationV(D)J recombination
VJ recombination, also known as somatic recombination, is a mechanism of genetic recombination in the early stages of immunoglobulin and T cell receptors production of the immune system...
, during which the different variable gene segments (those segments involved in antigen recognition) of TCRs and immunoglobulins are rearranged and unused segments removed. This introduces double-strand breaks between the required segments. These ends form hairpin loops and must be joined together to form a single strand (summarised in diagram, right). This joining is a very inaccurate process which results in the variable addition or subtraction of 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...
s and thus generates junctional diversity.
Generation of junctional diversity starts as the proteins, recombination activating gene
Recombination activating gene
The recombination activating genes encode enzymes that play an important role in the rearrangement and recombination of the genes of immunoglobulin and T cell receptor molecules during the process of VDJ recombination...
-1 and -2 (RAG1 and RAG2), along with DNA repair proteins, such as Artemis
DCLRE1C
Protein artemis is a protein that in humans is encoded by the DCLRE1C gene.- Function :This gene encodes a nuclear protein that is involved in VJ recombination and DNA repair...
, are responsible for single-stranded cleavage of the hairpin loops and addition of a series of palindromic
Palindrome
A palindrome is a word, phrase, number, or other sequence of units that can be read the same way in either direction, with general allowances for adjustments to punctuation and word dividers....
, 'P' nucleotides. Subsequently the enzyme, terminal deoxynucleotidyl transferase
Terminal Deoxynucleotidyl Transferase
Terminal deoxynucleotidyl transferase , also known as DNA nucleotidylexotransferase or terminal transferase, is a specialized DNA polymerase expressed in immature, pre-B, pre-T lymphoid cells, and acute lymphoblastic leukemia/lymphoma cells...
(TdT), adds further random ‘N’ nucleotides. The newly synthesised strands anneal to one another, but mismatches are common. Exonuclease
Exonuclease
Exonucleases are enzymes that work by cleaving nucleotides one at a time from the end of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3’ or the 5’ end occurs. Its close relative is the endonuclease, which cleaves phosphodiester bonds in the middle ...
s remove these unpaired nucleotides and the gaps are filled by DNA synthesis
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
and repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
machinery. Exonucleases may also cause shortening of this junction, however this process is still poorly understood.
Junctional diversity is liable to cause frame-shift mutations and thus production of non-functional proteins. Therefore
there is considerable waste involved in this process.