ATM Increases Activation-Induced Cytidine Deaminase Activity at Downstream S Regions during Class-Switch Recombination

Lyne Khair, Jeroen E. J. Guikema, Erin K. Linehan, Anna J. Ucher, Niek G. J. Leus, Colin Ogilvie, Zhenkun Lou, Carol E. Schrader, Janet Stavnezer

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14 Citations (Scopus)

Abstract

Activation-induced cytidine deaminase (AID) initiates Ab class-switch recombination (CSR) in activated B cells resulting in exchanging the IgH C region and improved Ab effector function. During CSR, AID instigates DNA double-strand break (DSB) formation in switch (S) regions located upstream of C region genes. DSBs are necessary for CSR, but improper regulation of DSBs can lead to chromosomal translocations that can result in B cell lymphoma. The protein kinase ataxia telangiectasia mutated (ATM) is an important proximal regulator of the DNA damage response (DDR), and translocations involving S regions are increased in its absence. ATM phosphorylates H2AX, which recruits other DNA damage response (DDR) proteins, including mediator of DNA damage checkpoint 1 (Mdc1) and p(53) binding protein 1 (53BP1), to sites of DNA damage. As these DDR proteins all function to promote repair and recombination of DSBs during CSR, we examined whether mouse splenic B cells deficient in these proteins would show alterations in S region DSBs when undergoing CSR. We find that in atm(-/-) cells S mu DSBs are increased, whereas DSBs in downstream S gamma regions are decreased. We also find that mutations in the unrearranged S gamma 3 segment are reduced in atm(-/-) cells. Our data suggest that ATM increases AID targeting and activity at downstream acceptor S regions during CSR and that in atm(-/-) cells Sm DSBs accumulate as they lack a recombination partner
Original languageEnglish
Pages (from-to)4887-4896
JournalJournal of immunology (Baltimore, Md.
Volume192
Issue number10
DOIs
Publication statusPublished - 2014

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