AID-dependent generation of resected double-strand DNA breaks and recruitment of Rad52/Rad51 in somatic hypermutation.
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.
Zan
Hong
H
Division of Molecular Immunology, Department of Pathology and Laboratory Medicine, Joan and Sanford I. Weill Medical College and Graduate School of Medical Sciences, Cornell University, New York, NY 10021, USA.
Wu
Xiaoping
X
Komori
Atsumasa
A
Holloman
William K
WK
Casali
Paolo
P
D001402:B-Lymphocytes / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051135:Rad51 Recombinase; D027041:Somatic Hypermutation, Immunoglobulin; D013601:T-Lymphocytes / Q000378:metabolism
D004268:DNA-Binding Proteins; C495153:RAD51 protein, human; D051135:Rad51 Recombinase