H2AX prevents DNA breaks from progressing to chromosome breaks and translocations.
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.
Franco
Sonia
S
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.
Gostissa
Monica
M
Zha
Shan
S
Lombard
David B
DB
Murphy
Michael M
MM
Zarrin
Ali A
AA
Yan
Catherine
C
Tepsuporn
Suprawee
S
Morales
Julio C
JC
Adams
Melissa M
MM
Lou
Zhenkun
Z
Bassing
Craig H
CH
Manis
John P
JP
Chen
Junjie
J
Carpenter
Phillip B
PB
Alt
Frederick W
FW
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)
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