AID-Dependent generation of resected double-strand DNA breaks and recruitment of Rad52/Rad51 in Somatic hypermutation

Hong Zan, Xiaoping Wu, Atsumasa Komori, William K. Holloman, Paolo Casali

Research output: Contribution to journalArticle

79 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)727-738
Number of pages12
JournalImmunity
Volume18
Issue number6
DOIs
StatePublished - Jun 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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