6oen

Structural highlights

Function

RAG2_MOUSE Core component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination. V(D)J recombination assembles a diverse repertoire of immunoglobulin and T-cell receptor genes in developing B and T-lymphocytes through rearrangement of different V (variable), in some cases D (diversity), and J (joining) gene segments. DNA cleavage by the RAG complex occurs in 2 steps: a first nick is introduced in the top strand immediately upstream of the heptamer, generating a 3'-hydroxyl group that can attack the phosphodiester bond on the opposite strand in a direct transesterification reaction, thereby creating 4 DNA ends: 2 hairpin coding ends and 2 blunt, 5'-phosphorylated ends. The chromatin structure plays an essential role in the V(D)J recombination reactions and the presence of histone H3 trimethylated at 'Lys-4' (H3K4me3) stimulates both the nicking and haipinning steps. The RAG complex also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. The introduction of DNA breaks by the RAG complex on one immunoglobulin allele induces ATM-dependent repositioning of the other allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. In the RAG complex, RAG2 is not the catalytic component but is required for all known catalytic activities mediated by RAG1. It probably acts as a sensor of chromatin state that recruits the RAG complex to H3K4me3.^{[1] [2] [3] [4] [5] [6]}

See Also

• High mobility group protein

References

1. ↑ Oettinger MA, Schatz DG, Gorka C, Baltimore D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. 1990 Jun 22;248(4962):1517-23. PMID:2360047
2. ↑ McBlane JF, van Gent DC, Ramsden DA, Romeo C, Cuomo CA, Gellert M, Oettinger MA. Cleavage at a V(D)J recombination signal requires only RAG1 and RAG2 proteins and occurs in two steps. Cell. 1995 Nov 3;83(3):387-95. PMID:8521468
3. ↑ Agrawal A, Schatz DG. RAG1 and RAG2 form a stable postcleavage synaptic complex with DNA containing signal ends in V(D)J recombination. Cell. 1997 Apr 4;89(1):43-53. PMID:9094713
4. ↑ West KL, Singha NC, De Ioannes P, Lacomis L, Erdjument-Bromage H, Tempst P, Cortes P. A direct interaction between the RAG2 C terminus and the core histones is required for efficient V(D)J recombination. Immunity. 2005 Aug;23(2):203-12. PMID:16111638 doi:http://dx.doi.org/10.1016/j.immuni.2005.07.004
5. ↑ Shimazaki N, Tsai AG, Lieber MR. H3K4me3 stimulates the V(D)J RAG complex for both nicking and hairpinning in trans in addition to tethering in cis: implications for translocations. Mol Cell. 2009 Jun 12;34(5):535-44. doi: 10.1016/j.molcel.2009.05.011. PMID:19524534 doi:http://dx.doi.org/10.1016/j.molcel.2009.05.011
6. ↑ Hewitt SL, Yin B, Ji Y, Chaumeil J, Marszalek K, Tenthorey J, Salvagiotto G, Steinel N, Ramsey LB, Ghysdael J, Farrar MA, Sleckman BP, Schatz DG, Busslinger M, Bassing CH, Skok JA. RAG-1 and ATM coordinate monoallelic recombination and nuclear positioning of immunoglobulin loci. Nat Immunol. 2009 Jun;10(6):655-64. doi: 10.1038/ni.1735. PMID:19448632 doi:http://dx.doi.org/10.1038/ni.1735
7. ↑ Chen X, Cui Y, Best RB, Wang H, Zhou ZH, Yang W, Gellert M. Cutting antiparallel DNA strands in a single active site. Nat Struct Mol Biol. 2020 Feb;27(2):119-126. doi: 10.1038/s41594-019-0363-2. Epub, 2020 Feb 3. PMID:32015552 doi:http://dx.doi.org/10.1038/s41594-019-0363-2