Regulation of hypermutation by activation-induced cytidine deaminase phosphorylation

Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8798-803. doi: 10.1073/pnas.0603272103. Epub 2006 May 24.

Abstract

Activation-induced cytidine deaminase (AID) initiates Ig class switch recombination and somatic hypermutation by producing U:G mismatches in DNA. These mismatches also have the potential to induce DNA damage including double-stranded breaks and chromosome translocations; therefore, strict regulation of AID is important for maintaining genomic stability. In addition to transcriptional regulation, it has been proposed that phosphorylation can also modulate AID activity. Using a combination of MS and immunochemical approaches we found that 5-15% of the AID expressed in activated B cells was phosphorylated at serine-38 (p38AID). This form of AID was enriched in the chromatin fraction in activated B cells, suggesting a role for phosphorylation in targeting AID to DNA. Consistent with this idea, serine-38 to alanine mutant AID (AID(S38A)) showed diminished somatic hypermutation activity on artificial and physiological DNA targets. We conclude that a small fraction of AID is phosphorylated in activated B cells and that the modified form contributes disproportionately to hypermutation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • B-Lymphocytes / enzymology
  • B-Lymphocytes / immunology
  • Cells, Cultured
  • Cytidine Deaminase / chemistry
  • Cytidine Deaminase / deficiency
  • Cytidine Deaminase / metabolism*
  • Fibroblasts / enzymology
  • Immunoglobulin Class Switching / immunology
  • Mice
  • Molecular Sequence Data
  • Phosphorylation
  • Phosphoserine / metabolism
  • Somatic Hypermutation, Immunoglobulin / genetics*

Substances

  • Phosphoserine
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase