H2AX prevents DNA breaks from progressing to chromosome breaks and translocations

Sonia Franco, Monica Gostissa, Shan Zha, David B. Lombard, Michael M. Murphy, Ali A. Zarrin, Catherine Yan, Suprawee Tepsuporn, Julio C. Morales, Melissa M. Adams, Zhenkun Lou, Craig H. Bassing, John P. Manis, Junjie Chen, Phillip B. Carpenter, Frederick W. Alt

Research output: Contribution to journalArticle

220 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)201-214
Number of pages14
JournalMolecular Cell
Volume21
Issue number2
DOIs
StatePublished - Jan 20 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Franco, S., Gostissa, M., Zha, S., Lombard, D. B., Murphy, M. M., Zarrin, A. A., Yan, C., Tepsuporn, S., Morales, J. C., Adams, M. M., Lou, Z., Bassing, C. H., Manis, J. P., Chen, J., Carpenter, P. B., & Alt, F. W. (2006). H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Molecular Cell, 21(2), 201-214. https://doi.org/10.1016/j.molcel.2006.01.005