ATM increases activation-induced cytidine deaminase activity at downstream S regions during class-switch recombination
Department of Microbiology and Physiological Systems
Medical Subject Headings
Animals; Ataxia Telangiectasia Mutated Proteins; Chromosomal Proteins, Non-Histone; Cytidine Deaminase; DNA Damage; DNA-Binding Proteins; Gene Rearrangement, B-Lymphocyte; Histones; Intracellular Signaling Peptides and Proteins; Mice; Mice, Knockout; Phosphorylation
Genetics and Genomics | Immunology and Infectious Disease
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 p53 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 Smu DSBs are increased, whereas DSBs in downstream Sgamma regions are decreased. We also find that mutations in the unrearranged Sgamma3 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 Smu DSBs accumulate as they lack a recombination partner.
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Citation: J Immunol. 2014 May 15;192(10):4887-96. doi: 10.4049/jimmunol.1303481. Epub 2014 Apr 11. Link to article on publisher's site
Khair, Lyne; Guikema, Jeroen E. J.; Linehan, Erin K.; Ucher, Anna J.; Leus, Niek G.J.; Ogilvie, Colin; Lou, Zhenkun; Schrader, Carol E.; and Stavnezer, Janet, "ATM increases activation-induced cytidine deaminase activity at downstream S regions during class-switch recombination" (2014). University of Massachusetts Medical School Faculty Publications. 701.