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AID-dependent generation of resected double-strand DNA breaks and recruitment of Rad52/Rad51 in somatic hypermutation.

TitleAID-dependent generation of resected double-strand DNA breaks and recruitment of Rad52/Rad51 in somatic hypermutation.
Publication TypeJournal Article
Year of Publication2003
AuthorsZan H, Wu X, Komori A, Holloman WK, Casali P
JournalImmunity
Volume18
Issue6
Pagination727-38
Date Published2003 Jun
ISSN1074-7613
KeywordsB-Lymphocytes, DNA-Binding Proteins, Humans, Rad51 Recombinase, Somatic Hypermutation, Immunoglobulin, T-Lymphocytes
Abstract

Somatic hypermutation (SHM) of immunoglobulin (Ig) genes appears to involve the generation of double-strand DNA breaks (DSBs) and their error-prone repair. Here we show that DSBs occur at a high frequency in unrearranged (germline) Ig variable (V) genes, BCL6 and c-MYC. These DSBs are blunt, target the mutational RGYW/RGY hotspot, and would be resolved through nonhomologous end-joining, as indicated by the presence of Ku70/Ku86 on these DNA ends. Upon CD40-induced expression of activation-induced cytidine deaminase (AID), DSBs increase in frequency and are resected to yield 5'- and 3'-protruding ends in hypermutating rearranged V genes, BCL6 and translocated c-MYC. 3'-protruding ends would direct DSB repair through homologous recombination, as indicated by their exclusive presence in S/G2 and recruitment of Rad52/Rad51, leading to SHM, upon mispair by error-prone DNA polymerases modulated by crosslinking of the B cell receptor for antigen.

Alternate JournalImmunity
PubMed ID12818155
Grant ListAG 13910 / AG / NIA NIH HHS / United States
AI 07621 / AI / NIAID NIH HHS / United States
AI 45011 / AI / NIAID NIH HHS / United States
AR 40908 / AR / NIAMS NIH HHS / United States
GM 42482 / GM / NIGMS NIH HHS / United States

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