Amino-terminal phosphorylation of activation-induced cytidine deaminase suppresses c-myc/IgH translocation.
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.
Laboratory of Molecular Immunology, Rockefeller University, 1230 York Ave., New York, NY 10065, USA.
Anna
A
Gazumyan
Ksenia
K
Timachova
Grace
G
Yuen
Edward
E
Siden
Michela
M
Di Virgilio
Eileen M
EM
Woo
Brian T
BT
Chait
Bernardo
B
Reina San-Martin
Michel C
MC
Nussenzweig
Kevin M
KM
McBride
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D003564:Cytidine Deaminase / Q000737:chemistry* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D017578:Immunoglobulin Class Switching / Q000187:drug effects; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D011995:Recombination, Genetic / Q000187:drug effects / Q000235:genetics; D027041:Somatic Hypermutation, Immunoglobulin / Q000187:drug effects / Q000235:genetics; D014178:Translocation, Genetic / Q000187:drug effects; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D004791:Enzyme Inhibitors; D007143:Immunoglobulin Heavy Chains; D050505:Mutant Proteins; D016271:Proto-Oncogene Proteins c-myc; D010768:Phosphoserine; D054648:Protein Phosphatase 2; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase