Amino-Terminal Phosphorylation of Activation-Induced Cytidine Deaminase Suppresses c-myc/IgH Translocation

Abstract

Activation-induced cytidine deaminase (AID) is a mutator enzyme that initiates class switch recombination and somatic hypermutation of immunoglobulin genes (Ig) in B lymphocytes. However, AID also produces off-target DNA damage, including mutations in oncogenes and double-stranded breaks that can serve as substrates for oncogenic chromosomal translocations. AID is strictly regulated by a number of mechanisms, including phosphorylation at serine 38 and threonine 140, which increase activity. Here we show that phosphorylation can also suppress AID activity in vivo. Serine 3 is a novel phospho-acceptor which, when mutated to alanine, leads to increased class switching and c-myc/IgH translocations without affecting AID levels or catalytic activity. Conversely, increasing AID phosphorylation specifically on serine 3 by interfering with serine/threonine protein phosphatase 2A (PP2A) leads to decreased class switching. We conclude that AID activity and its oncogenic potential can be downregulated by phosphorylation of serine 3 and that this process is controlled by PP2A.

ACKNOWLEDGMENTS

We thank the members of the Nussenzweig lab and F. N. Papavasiliou for discussion, Sara Davis and Diana Yens for manuscript reading, Tom Eisenreich for mouse breeding, and Klara Velizon for cell sorting.

This work was funded in part by NIH grant R01AI03752616 to M.C.N. and RR00862 to B.T.C. M.C.N. is an HHMI investigator. M.D.V. is a fellow of the American-Italian Cancer Foundation.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00349-10.