Activation induced deaminase C-terminal domain links DNA breaks to end protection and repair during class switch recombination

Proc Natl Acad Sci U S A. 2014 Mar 18;111(11):E988-97. doi: 10.1073/pnas.1320486111. Epub 2014 Mar 3.

Abstract

Activation-induced deaminase (AID) triggers antibody class switch recombination (CSR) in B cells by initiating DNA double strand breaks that are repaired by nonhomologous end-joining pathways. A role for AID at the repair step is unclear. We show that specific inactivation of the C-terminal AID domain encoded by exon 5 (E5) allows very efficient deamination of the AID target regions but greatly impacts the efficiency and quality of subsequent DNA repair. Specifically eliminating E5 not only precludes CSR but also, causes an atypical, enzymatic activity-dependent dominant-negative effect on CSR. Moreover, the E5 domain is required for the formation of AID-dependent Igh-cMyc chromosomal translocations. DNA breaks at the Igh switch regions induced by AID lacking E5 display defective end joining, failing to recruit DNA damage response factors and undergoing extensive end resection. These defects lead to nonproductive resolutions, such as rearrangements and homologous recombination that can antagonize CSR. Our results can explain the autosomal dominant inheritance of AID variants with truncated E5 in patients with hyper-IgM syndrome 2 and establish that AID, through the E5 domain, provides a link between DNA damage and repair during CSR.

Keywords: antibody gene diversification; isotype switching; somatic hypermutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • B-Lymphocytes / immunology
  • Blotting, Western
  • Cell Line
  • Chromatin Immunoprecipitation
  • Cytidine Deaminase / metabolism*
  • DNA Breaks*
  • DNA End-Joining Repair / genetics
  • DNA End-Joining Repair / physiology*
  • Humans
  • Immunoglobulin Class Switching / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA, Small Interfering / genetics
  • Translocation, Genetic / genetics
  • Uracil-DNA Glycosidase / genetics

Substances

  • RNA, Small Interfering
  • Uracil-DNA Glycosidase
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase