Title | MOF phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Gupta A, Hunt CR, Hegde ML, Chakraborty S, Chakraborty S, Udayakumar D, Horikoshi N, Singh M, Ramnarain DB, Hittelman WN, Namjoshi S, Asaithamby A, Hazra TK, Ludwig T, Pandita RK, Tyler JK, Pandita TK |
Journal | Cell Rep |
Volume | 8 |
Issue | 1 |
Pagination | 177-89 |
Date Published | 2014 Jul 10 |
ISSN | 2211-1247 |
Keywords | Animals, Ataxia Telangiectasia Mutated Proteins, BRCA1 Protein, Cell Line, Tumor, DNA Breaks, Double-Stranded, G1 Phase Cell Cycle Checkpoints, G2 Phase Cell Cycle Checkpoints, HEK293 Cells, Histone Acetyltransferases, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mutation, Phosphorylation, Recombinational DNA Repair, Tumor Suppressor p53-Binding Protein 1 |
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. |
DOI | 10.1016/j.celrep.2014.05.044 |
Alternate Journal | Cell Rep |
PubMed ID | 24953651 |
PubMed Central ID | PMC4300955 |
Grant List | CA154320 / CA / NCI NIH HHS / United States CA129537 / CA / NCI NIH HHS / United States |
Related Lab:
Related Faculty:
Jessica K. Tyler, Ph.D.