TY - JOUR
T1 - MOF phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice
AU - Gupta, Arun
AU - Hunt, Clayton R.
AU - Hegde, Muralidhar L.
AU - Chakraborty, Sharmistha
AU - Udayakumar, Durga
AU - Horikoshi, Nobuo
AU - Singh, Mayank
AU - Ramnarain, Deepti B.
AU - Hittelman, Walter N.
AU - Namjoshi, Sarita
AU - Asaithamby, Aroumougame
AU - Hazra, Tapas K.
AU - Ludwig, Thomas
AU - Pandita, Raj K.
AU - Tyler, Jessica K.
AU - Pandita, Tej K.
N1 - Funding Information:
We thank Maria Jasin, Simmon Boulton, Daniel Durocher, Matthew Porteus, Tanya Paull, Yali Duo, and Simon Powell for providing reagents. Sincere thanks are due to Daniel Durocher, Andre Nussenzweig, and to members of T.K.P.’s laboratory for critical reading and suggestions for the manuscript. This work has been supported by NIH grants CA129537 and CA154320.
PY - 2014/7/10
Y1 - 2014/7/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84904070920&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904070920&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2014.05.044
DO - 10.1016/j.celrep.2014.05.044
M3 - Article
C2 - 24953651
AN - SCOPUS:84904070920
SN - 2211-1247
VL - 8
SP - 177
EP - 189
JO - Cell Reports
JF - Cell Reports
IS - 1
ER -