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

doi:10.1016/j.celrep.2014.05.044

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^*

^*Corresponding author for this work

Radiation Oncology

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

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 language	English (US)
Pages (from-to)	177-189
Number of pages	13
Journal	Cell reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2014.05.044
State	Published - Jul 10 2014

Funding

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.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2014.05.044

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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

@article{cdb6a26762df4ae0be36222230a7d266,

title = "MOF phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice",

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.",

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

note = "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.{\textquoteright}s laboratory for critical reading and suggestions for the manuscript. This work has been supported by NIH grants CA129537 and CA154320. ",

year = "2014",

month = jul,

day = "10",

doi = "10.1016/j.celrep.2014.05.044",

language = "English (US)",

volume = "8",

pages = "177--189",

journal = "Cell reports",

issn = "2211-1247",

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Gupta, A, Hunt, CR, Hegde, ML, 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 2014, 'MOF phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice', Cell reports, vol. 8, no. 1, pp. 177-189. https://doi.org/10.1016/j.celrep.2014.05.044

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.

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JO - Cell reports

JF - Cell reports

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ER -

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

Abstract

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ASJC Scopus subject areas

UN SDGs

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