Immunoglobulin somatic hypermutation: Double-strand DNA breaks, AID and error-prone DNA repair

Xiaoping Wu, Junli Feng, Atsumasa Komori, Edmund C. Kim, Hong Zan, Paolo Casali

Research output: Contribution to journalReview articlepeer-review

36 Scopus citations

Abstract

Somatic hypermutation (SHM) is critical for antibody affinity maturation and the generation of memory B cells. Somatic mutations consist mainly of single nucleotide changes with rare insertions and deletions. Such changes would be introduced during error-prone repair of lesions involving single-strand DNA breaks (SSBs) or, more likely, double-strand DNA breaks (DSBs), as DSBs occur exclusively in genes that have the potentials to undergo SHM. In the human, such genes include Ig V, BCL6, and c-MYC. In these germline genes, DSBs are blunt. In rearranged Ig V, BCL6, and translocated c-MYC genes, blunt DSBs are processed to yield resected DNA ends. This process is dependent on the expression of activation-induced cytidine deaminase (AID), which is selectively expressed upon CD40-signaling in hypermutating B cells. CD40-induced and AID-dependent free 5′- and 3′-staggered DNA ends critically channel the repair of DSBs through the homologous recombination (HR) repair pathway. During HR, the modulation of critical translesion DNA polymerases, as signaled by cross-linking of the B cell receptor (BCR) for antigen, leads to the insertions of mismatches, i.e., mutations. The nature of DSBs, the possible roles of AID in the modification of DSBs and that of the translesion DNA polymerases ζ and ι in the subsequent repair process that lead to the insertions of mutations are discussed here within the context of an integrated model of SHM.

Original languageEnglish (US)
Pages (from-to)235-246
Number of pages12
JournalJournal of Clinical Immunology
Volume23
Issue number4
DOIs
StatePublished - Jul 2003
Externally publishedYes

Keywords

  • AID
  • DSBs
  • Error-prone DNA repair
  • SHM

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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