title: ATM increases activation-induced cytidine deaminase activity at downstream S regions during class-switch recombination.
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 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 Sμ DSBs are increased, whereas DSBs in downstream Sγ regions are decreased. We also find that mutations in the unrearranged Sγ3 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 Sμ DSBs accumulate as they lack a recombination partner.
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Lyne
authors.initials: L
authors.lastname: Khair
authors.forename: Jeroen E J
authors.initials: JE
authors.lastname: Guikema
authors.forename: Erin K
authors.initials: EK
authors.lastname: Linehan
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Ucher
authors.forename: Niek G J
authors.initials: NG
authors.lastname: Leus
authors.forename: Colin
authors.initials: C
authors.lastname: Ogilvie
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
authors.forename: Carol E
authors.initials: CE
authors.lastname: Schrader
authors.forename: Janet
authors.initials: J
authors.lastname: Stavnezer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000276:immunology; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000276:immunology; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology*; D004249:DNA Damage / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics / Q000276:immunology*; D006657:Histones / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D000071857:Tumor Suppressor p53-Binding Protein 1; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D003564:Cytidine Deaminase; D004268:DNA-Binding Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; D000098830:AICDA (Activation-Induced Cytidine Deaminase); C508937:MDC1 protein, mouse; C498302:Trp53bp1 protein, mouse; C576325:Atm protein, mouse; C475961:gamma-H2AX protein, mouse
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