TY - JOUR
T1 - Phosphorylation promotes activation-induced cytidine deaminase activity at the Myc oncogene
AU - Mu, Yunxiang
AU - Zelazowska, Monika A.
AU - McBride, Kevin M.
N1 - Funding Information:
We acknowledge the University of Texas M.D. Anderson Cancer Center (UTM DACC) Research Animal Support Facility (NIH CA16672), flow cytometry core, and molecular biology core. This research was supported by the Welch Foundation (G-1847), Three Strohm Sisters Family Foundation, and UTMDACC Center for Environmental and Molecular Carcinogenesis and Leukemia Specialized Program of Research Excellence (NIH CA100632). Y. Mu was supported by a fellowship from the UTMDACC Center for Cancer Epigenetics. The authors declare no competing financial interests.
Publisher Copyright:
© 2017 Mu et al.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Activation-induced cytidine deaminase (AID) is a mutator enzyme that targets immunoglobulin (Ig) genes to initiate antibody somatic hypermutation (SHM) and class switch recombination (CSR). Off-target AID association also occurs, which causes oncogenic mutations and chromosome rearrangements. However, AID occupancy does not directly correlate with DNA damage, suggesting that factors beyond AID association contribute to mutation targeting. CSR and SHM are regulated by phosphorylation on AID serine38 (pS38), but the role of pS38 in off-target activity has not been evaluated. We determined that lithium, a clinically used therapeutic, induced high AID pS38 levels. Using lithium and an AID-S38 phospho mutant, we compared the role of pS38 in AID activity at the Ig switch region and off-target Myc gene. We found that deficient pS38 abated AID chromatin association and CSR but not mutation at Myc. Enhanced pS38 elevated Myc translocation and mutation frequency but not CSR or Ig switch region mutation. Thus, AID activity can be differentially targeted by phosphorylation to induce oncogenic lesions.
AB - Activation-induced cytidine deaminase (AID) is a mutator enzyme that targets immunoglobulin (Ig) genes to initiate antibody somatic hypermutation (SHM) and class switch recombination (CSR). Off-target AID association also occurs, which causes oncogenic mutations and chromosome rearrangements. However, AID occupancy does not directly correlate with DNA damage, suggesting that factors beyond AID association contribute to mutation targeting. CSR and SHM are regulated by phosphorylation on AID serine38 (pS38), but the role of pS38 in off-target activity has not been evaluated. We determined that lithium, a clinically used therapeutic, induced high AID pS38 levels. Using lithium and an AID-S38 phospho mutant, we compared the role of pS38 in AID activity at the Ig switch region and off-target Myc gene. We found that deficient pS38 abated AID chromatin association and CSR but not mutation at Myc. Enhanced pS38 elevated Myc translocation and mutation frequency but not CSR or Ig switch region mutation. Thus, AID activity can be differentially targeted by phosphorylation to induce oncogenic lesions.
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U2 - 10.1084/jem.20170468
DO - 10.1084/jem.20170468
M3 - Article
C2 - 29122947
AN - SCOPUS:85036584302
SN - 0022-1007
VL - 214
SP - 3543
EP - 3552
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 12
ER -