MOF Phosphorylation by ATM Regulates 53BP1-Mediated Double-Strand Break Repair Pathway Choice

• DOI: 10.1016/j.celrep.2014.05.044
• Publication Date: 2014-06-19T11:55:03Z
• Authors: Arun Gupta; Clayton R. Hunt; Muralidhar L. Hegde; Sharmistha Chakra...; Durga Udayakumar; Nobuo Horikoshi; Mayank Singh; Deepti B. Ramnarain; Walter N. Hittelman; Sarita Namjoshi; Aroumougame Asait...; Tapas K. Hazra; Thomas Ludwig; Raj K. Pandita; Jessica K. Tyler; Tej K. Pandita
• Keywords: Non-homologous end joining

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 phosphorylated colocalizes with γ-H2AX, ATM, 53BP1 foci. Mutation site (MOF-T392A) impedes in S G2 but not G1 cells. Expression MOF-T392A also blocks reduction DSB-associated seen wild-type S/G2 cells, resulting enhanced reduced BRCA1 association. Decreased levels at DSB sites correlates defective repairosome formation, HR repair, decreased cell survival following irradiation. These data support model whereby ATM-mediated MOF-T392 modulates function to facilitate subsequent recruitment proteins, uncovering regulatory role for pathway during phase.