title: H2AX prevents DNA breaks from progressing to chromosome breaks and translocations.
abstract: Histone H2AX promotes DNA double-strand break (DSB) repair and immunoglobulin heavy chain (IgH) class switch recombination (CSR) in B-lymphocytes. CSR requires activation-induced cytidine deaminase (AID) and involves joining of DSB intermediates by end joining. We find that AID-dependent IgH locus chromosome breaks occur at high frequency in primary H2AX-deficient B cells activated for CSR and that a substantial proportion of these breaks participate in chromosomal translocations. Moreover, activated B cells deficient for ATM, 53BP1, or MDC1, which interact with H2AX during the DSB response, show similarly increased IgH locus breaks and translocations. Thus, our findings implicate a general role for these factors in promoting end joining and thereby preventing DSBs from progressing into chromosomal breaks and translocations. As cellular p53 status does not markedly influence the frequency of such events, our results also have implications for how p53 and the DSB response machinery cooperate to suppress generation of lymphomas with oncogenic translocations.
authors.affiliation: Howard Hughes Medical Institute, The Children's Hospital, Department of Genetics, Harvard Medical School and the CBR Institute for Biomedical Research, Boston, Massachusetts 02115, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Franco
authors.forename: Monica
authors.initials: M
authors.lastname: Gostissa
authors.forename: Shan
authors.initials: S
authors.lastname: Zha
authors.forename: David B
authors.initials: DB
authors.lastname: Lombard
authors.forename: Michael M
authors.initials: MM
authors.lastname: Murphy
authors.forename: Ali A
authors.initials: AA
authors.lastname: Zarrin
authors.forename: Catherine
authors.initials: C
authors.lastname: Yan
authors.forename: Suprawee
authors.initials: S
authors.lastname: Tepsuporn
authors.forename: Julio C
authors.initials: JC
authors.lastname: Morales
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Adams
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
authors.forename: Craig H
authors.initials: CH
authors.lastname: Bassing
authors.forename: John P
authors.initials: JP
authors.lastname: Manis
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Carpenter
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019457:Chromosome Breakage; D003564:Cytidine Deaminase / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology*; D006657:Histones / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017578:Immunoglobulin Class Switching; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D017404:In Situ Hybridization, Fluorescence; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D003564:Cytidine Deaminase; D006657:Histones; D007143:Immunoglobulin Heavy Chains; D016159:Tumor Suppressor Protein p53; D000098830:AICDA (Activation-Induced Cytidine Deaminase); C475961:gamma-H2AX protein, mouse