DNA cleavage of a cryptic recombination signal sequence by RAG1 and RAG2. Implications for partial V(H) gene replacement

The Journal of Biological Chemistry
Negar S RahmanKarla K Rodgers

Abstract

Antibody and T cell receptor genes are assembled from gene segments by V(D)J recombination to produce an almost infinitely diverse repertoire of antigen specificities. Recombination is initiated by cleavage of conserved recombination signal sequences (RSS) by RAG1 and RAG2 during lymphocyte development. Recent evidence demonstrates that recombination can occur at noncanonical RSS sites within Ig genes or at other loci, outside the context of normal lymphocyte receptor gene rearrangement. We have characterized the ability of the RAG proteins to bind and cleave a cryptic RSS (cRSS) located within an Ig V(H) gene segment. The RAG proteins bound with sequence specificity to either the consensus RSS or the cRSS. The RAG proteins nick the cRSS on both the top and bottom strands, thereby bypassing the formation of the DNA hairpin intermediate observed in RAG cleavage of canonical RSS substrates. We propose that the RAG proteins may utilize an alternative mechanism for double-stranded DNA cleavage, depending on the substrate sequence. These results have implications for further diversification of the antigen receptor repertoire as well as the role of the RAG proteins in genomic instability.

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Citations

Jan 26, 2012·The Journal of Biological Chemistry·Mridula Nambiar, Sathees C Raghavan
Feb 1, 2008·BMC Biochemistry·Pallabi DeKarla K Rodgers
Feb 24, 2009·Journal of Molecular Biology·Shuying ZhaoKarla K Rodgers
Feb 14, 2015·Protein Science : a Publication of the Protein Society·Jennifer N ByrumKarla K Rodgers
Aug 25, 2015·Nature Immunology·Malay MandalMarcus R Clark
Aug 26, 2015·Molecular and Cellular Biology·Keerthi Shetty, David G Schatz
Jan 22, 2008·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Eva HegedüsGábor Szabó
Jan 12, 2008·The Journal of Biological Chemistry·Ming Zhang, Patrick C Swanson
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Feb 10, 2017·The Journal of Experimental Medicine·Philipp C RommelDavide F Robbiani
Nov 20, 2008·The Journal of Immunology : Official Journal of the American Association of Immunologists·Nancy S LongoPeter E Lipsky

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