101. MOF phosphorylation by ATM regulates 53BP1-mediated DSB repair pathway choice
- Author
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Gupta, Arun, Hunt, Clayton R., Hegdec, Muralidhar L., Chakraborty, Sharmistha, Udayakumar, Durga, Horikoshi, Nobuo, Singh1, Mayank, Ramnarain, Deepti B., Hittelman, Walter N., Namjoshi, Sarita, Asaithamby, Aroumougame, Hazra, Tapas K., Ludwig, Thomas, Pandita, Raj K., Tyler, Jessica K., and Pandita, Tej K.
- Subjects
BRCA1 Protein ,fungi ,Intracellular Signaling Peptides and Proteins ,Recombinational DNA Repair ,Ataxia Telangiectasia Mutated Proteins ,G1 Phase Cell Cycle Checkpoints ,Article ,G2 Phase Cell Cycle Checkpoints ,enzymes and coenzymes (carbohydrates) ,Mice ,HEK293 Cells ,Cell Line, Tumor ,Mutation ,Animals ,Humans ,DNA Breaks, Double-Stranded ,Phosphorylation ,Tumor Suppressor p53-Binding Protein 1 ,Histone Acetyltransferases - 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.
- Published
- 2014