TY - JOUR
T1 - AID-Dependent generation of resected double-strand DNA breaks and recruitment of Rad52/Rad51 in Somatic hypermutation
AU - Zan, Hong
AU - Wu, Xiaoping
AU - Komori, Atsumasa
AU - Holloman, William K.
AU - Casali, Paolo
N1 - Funding Information:
We thank Shefali Shah for her technical help. This work was supported by N.I.H. grants AI 45011, AR 40908, AG 13910, AI 07621 (to P.C.), and GM 42482 (to W.K.H).
PY - 2003/6/1
Y1 - 2003/6/1
N2 - 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.
AB - 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.
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U2 - 10.1016/S1074-7613(03)00151-1
DO - 10.1016/S1074-7613(03)00151-1
M3 - Article
C2 - 12818155
AN - SCOPUS:0038771252
SN - 1074-7613
VL - 18
SP - 727
EP - 738
JO - Immunity
JF - Immunity
IS - 6
ER -