Specific recruitment of protein kinase A to the immunoglobulin locus regulates class-switch recombination

Nat Immunol. 2009 Apr;10(4):420-6. doi: 10.1038/ni.1708. Epub 2009 Feb 22.


Immunoglobulin class-switch recombination (CSR) requires activation-induced cytidine deaminase (AID). Deamination of DNA by AID in transcribed switch (S) regions leads to double-stranded breaks in DNA that serve as obligatory CSR intermediates. Here we demonstrate that the catalytic and regulatory subunits of protein kinase A (PKA) were specifically recruited to S regions to promote the localized phosphorylation of AID, which led to binding of replication protein A and subsequent propagation of the CSR cascade. Accordingly, inactivation of PKA resulted in considerable disruption of CSR because of decreased AID phosphorylation and recruitment of replication protein A to S regions. We propose that PKA nucleates the formation of active AID complexes specifically on S regions to generate the high density of DNA lesions required for CSR.

Publication types

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

MeSH terms

  • Animals
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / immunology*
  • Cytidine Deaminase / immunology*
  • DNA Breaks, Double-Stranded
  • Immunoglobulin Class Switching*
  • Mice
  • Mice, Mutant Strains
  • Phosphorylation
  • Protein Binding
  • Recombination, Genetic / immunology*
  • Replication Protein A / immunology*
  • Retroviridae Infections / immunology


  • Replication Protein A
  • Cyclic AMP-Dependent Protein Kinases
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase