MOF phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice

Arun Gupta, Clayton R. Hunt, Muralidhar L. Hegde, Sharmistha Chakraborty, Durga Udayakumar, Nobuo Horikoshi, Mayank Singh, Deepti B. Ramnarain, Walter N. Hittelman, Sarita Namjoshi, Aroumougame Asaithamby, Tapas K. Hazra, Thomas Ludwig, Raj K. Pandita, Jessica K. Tyler, Tej K. Pandita

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Abstract

Cell-cycle phase is a critical determinant of the choice between DNA damage repair by nonhomologous end-joining (NHEJ) or homologous recombination (HR). Here, we report that double-strand breaks (DSBs) induce ATM-dependent MOF (a histone H4 acetyl-transferase) phosphorylation (p-T392-MOF) and that phosphorylated MOF colocalizes with γ-H2AX, ATM, and 53BP1 foci. Mutation of the phosphorylation site (MOF-T392A) impedes DNA repair in S and G2 phase but not G1 phase cells. Expression of MOF-T392A also blocks the reduction in DSB-associated 53BP1 seen in wild-type S/G2 phase cells, resulting in enhanced 53BP1 and reduced BRCA1 association. Decreased BRCA1 levels at DSB sites correlates with defective repairosome formation, reduced HR repair, and decreased cell survival following irradiation. These data support a model whereby ATM-mediated MOF-T392 phosphorylation modulates 53BP1 function to facilitate the subsequent recruitment of HR repair proteins, uncovering a regulatory role for MOF in DSB repair pathway choice during S/G2 phase.

Original languageEnglish (US)
Pages (from-to)177-189
Number of pages13
JournalCell Reports
Volume8
Issue number1
DOIs
StatePublished - Jul 10 2014

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Gupta, A., Hunt, C. R., Hegde, M. L., Chakraborty, S., Udayakumar, D., Horikoshi, N., Singh, M., Ramnarain, D. B., Hittelman, W. N., Namjoshi, S., Asaithamby, A., Hazra, T. K., Ludwig, T., Pandita, R. K., Tyler, J. K., & Pandita, T. K. (2014). MOF phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice. Cell Reports, 8(1), 177-189. https://doi.org/10.1016/j.celrep.2014.05.044