53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions

Elsa Callen; Michela Di Virgilio; Michael J. Kruhlak; Maria Nieto-Soler; Nancy Wong; Hua Tang Chen; Robert B. Faryabi; Federica Polato; Margarida Santos; Linda M. Starnes; Duane R. Wesemann; Ji Eun Lee; Anthony Tubbs; Barry P. Sleckman; Jeremy A. Daniel; Kai Ge; Frederick W. Alt; Oscar Fernandez-Capetillo; Michel C. Nussenzweig; André Nussenzweig

doi:10.1016/j.cell.2013.05.023

53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions

Elsa Callen, Michela Di Virgilio, Michael J. Kruhlak, Maria Nieto-Soler, Nancy Wong, Hua Tang Chen, Robert B. Faryabi, Federica Polato, Margarida Santos, Linda M. Starnes, Duane R. Wesemann, Ji Eun Lee, Anthony Tubbs, Barry P. Sleckman, Jeremy A. Daniel, Kai Ge, Frederick W. Alt, Oscar Fernandez-Capetillo, Michel C. Nussenzweig, André Nussenzweig

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264 Scopus citations

Abstract

The DNA damage response (DDR) protein 53BP1 protects DNA ends from excessive resection in G1, and thereby favors repair by nonhomologous end-joining (NHEJ) as opposed to homologous recombination (HR). During S phase, BRCA1 antagonizes 53BP1 to promote HR. The pro-NHEJ and antirecombinase functions of 53BP1 are mediated in part by RIF1, the only known factor that requires 53BP1 phosphorylation for its recruitment to double-strand breaks (DSBs). Here, we show that a 53BP1 phosphomutant, 53BP1^8A, comprising alanine substitutions of the eight most N-terminal S/TQ phosphorylation sites, mimics 53BP1 deficiency by restoring genome stability in BRCA1-deficient cells yet behaves like wild-type 53BP1 with respect to immunoglobulin class switch recombination (CSR). 53BP1^8A recruits RIF1 but fails to recruit the DDR protein PTIP to DSBs, and disruption of PTIP phenocopies 53BP1^8A. We conclude that 53BP1 promotes productive CSR and suppresses mutagenic DNA repair through distinct phosphodependent interactions with RIF1 and PTIP.

Original language	English (US)
Pages (from-to)	1266-1280
Number of pages	15
Journal	Cell
Volume	153
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2013.05.023
State	Published - Jun 6 2013
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2013.05.023

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Callen, E., Di Virgilio, M., Kruhlak, M. J., Nieto-Soler, M., Wong, N., Chen, H. T., Faryabi, R. B., Polato, F., Santos, M., Starnes, L. M., Wesemann, D. R., Lee, J. E., Tubbs, A., Sleckman, B. P., Daniel, J. A., Ge, K., Alt, F. W., Fernandez-Capetillo, O., Nussenzweig, M. C., & Nussenzweig, A. (2013). 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions. Cell, 153(6), 1266-1280. https://doi.org/10.1016/j.cell.2013.05.023

Callen, E, Di Virgilio, M, Kruhlak, MJ, Nieto-Soler, M, Wong, N, Chen, HT, Faryabi, RB, Polato, F, Santos, M, Starnes, LM, Wesemann, DR, Lee, JE, Tubbs, A, Sleckman, BP, Daniel, JA, Ge, K, Alt, FW, Fernandez-Capetillo, O, Nussenzweig, MC & Nussenzweig, A 2013, '53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions', Cell, vol. 153, no. 6, pp. 1266-1280. https://doi.org/10.1016/j.cell.2013.05.023

@article{a6ae6ab17df44555b00c61b2c6c308b5,

title = "53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions",

abstract = "The DNA damage response (DDR) protein 53BP1 protects DNA ends from excessive resection in G1, and thereby favors repair by nonhomologous end-joining (NHEJ) as opposed to homologous recombination (HR). During S phase, BRCA1 antagonizes 53BP1 to promote HR. The pro-NHEJ and antirecombinase functions of 53BP1 are mediated in part by RIF1, the only known factor that requires 53BP1 phosphorylation for its recruitment to double-strand breaks (DSBs). Here, we show that a 53BP1 phosphomutant, 53BP18A, comprising alanine substitutions of the eight most N-terminal S/TQ phosphorylation sites, mimics 53BP1 deficiency by restoring genome stability in BRCA1-deficient cells yet behaves like wild-type 53BP1 with respect to immunoglobulin class switch recombination (CSR). 53BP18A recruits RIF1 but fails to recruit the DDR protein PTIP to DSBs, and disruption of PTIP phenocopies 53BP18A. We conclude that 53BP1 promotes productive CSR and suppresses mutagenic DNA repair through distinct phosphodependent interactions with RIF1 and PTIP.",

author = "Elsa Callen and {Di Virgilio}, Michela and Kruhlak, {Michael J.} and Maria Nieto-Soler and Nancy Wong and Chen, {Hua Tang} and Faryabi, {Robert B.} and Federica Polato and Margarida Santos and Starnes, {Linda M.} and Wesemann, {Duane R.} and Lee, {Ji Eun} and Anthony Tubbs and Sleckman, {Barry P.} and Daniel, {Jeremy A.} and Kai Ge and Alt, {Frederick W.} and Oscar Fernandez-Capetillo and Nussenzweig, {Michel C.} and Andr{\'e} Nussenzweig",

note = "Funding Information: We thank all members of the A. Nussenzweig lab and Davide Robbiani for discussions; Titia de Lange for RIF1f/f mice; Susan Sharrow for flow cytometry; and Sandy Chang for the TRF2 shRNA construct. M.C.N., F.W.A and O.F.-C. are HHMI investigators. D.R.W. was supported by NIH grants AI89972, the American Association of Allergy Asthma and Immunology and CSL Behring, and a Career Award for Medical Scientists (Burroughs Wellcome Fund). This work was supported by the Intramural Research Program of the NIH, the National Cancer Institute, and the Center for Cancer Research, and by a Department of Defense grant to A.N. (BC102335). ",

year = "2013",

month = jun,

day = "6",

doi = "10.1016/j.cell.2013.05.023",

language = "English (US)",

volume = "153",

pages = "1266--1280",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "6",

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TY - JOUR

T1 - 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions

AU - Callen, Elsa

AU - Di Virgilio, Michela

AU - Kruhlak, Michael J.

AU - Nieto-Soler, Maria

AU - Wong, Nancy

AU - Chen, Hua Tang

AU - Faryabi, Robert B.

AU - Polato, Federica

AU - Santos, Margarida

AU - Starnes, Linda M.

AU - Wesemann, Duane R.

AU - Lee, Ji Eun

AU - Tubbs, Anthony

AU - Sleckman, Barry P.

AU - Daniel, Jeremy A.

AU - Ge, Kai

AU - Alt, Frederick W.

AU - Fernandez-Capetillo, Oscar

AU - Nussenzweig, Michel C.

AU - Nussenzweig, André

N1 - Funding Information: We thank all members of the A. Nussenzweig lab and Davide Robbiani for discussions; Titia de Lange for RIF1f/f mice; Susan Sharrow for flow cytometry; and Sandy Chang for the TRF2 shRNA construct. M.C.N., F.W.A and O.F.-C. are HHMI investigators. D.R.W. was supported by NIH grants AI89972, the American Association of Allergy Asthma and Immunology and CSL Behring, and a Career Award for Medical Scientists (Burroughs Wellcome Fund). This work was supported by the Intramural Research Program of the NIH, the National Cancer Institute, and the Center for Cancer Research, and by a Department of Defense grant to A.N. (BC102335).

PY - 2013/6/6

Y1 - 2013/6/6

N2 - The DNA damage response (DDR) protein 53BP1 protects DNA ends from excessive resection in G1, and thereby favors repair by nonhomologous end-joining (NHEJ) as opposed to homologous recombination (HR). During S phase, BRCA1 antagonizes 53BP1 to promote HR. The pro-NHEJ and antirecombinase functions of 53BP1 are mediated in part by RIF1, the only known factor that requires 53BP1 phosphorylation for its recruitment to double-strand breaks (DSBs). Here, we show that a 53BP1 phosphomutant, 53BP18A, comprising alanine substitutions of the eight most N-terminal S/TQ phosphorylation sites, mimics 53BP1 deficiency by restoring genome stability in BRCA1-deficient cells yet behaves like wild-type 53BP1 with respect to immunoglobulin class switch recombination (CSR). 53BP18A recruits RIF1 but fails to recruit the DDR protein PTIP to DSBs, and disruption of PTIP phenocopies 53BP18A. We conclude that 53BP1 promotes productive CSR and suppresses mutagenic DNA repair through distinct phosphodependent interactions with RIF1 and PTIP.

AB - The DNA damage response (DDR) protein 53BP1 protects DNA ends from excessive resection in G1, and thereby favors repair by nonhomologous end-joining (NHEJ) as opposed to homologous recombination (HR). During S phase, BRCA1 antagonizes 53BP1 to promote HR. The pro-NHEJ and antirecombinase functions of 53BP1 are mediated in part by RIF1, the only known factor that requires 53BP1 phosphorylation for its recruitment to double-strand breaks (DSBs). Here, we show that a 53BP1 phosphomutant, 53BP18A, comprising alanine substitutions of the eight most N-terminal S/TQ phosphorylation sites, mimics 53BP1 deficiency by restoring genome stability in BRCA1-deficient cells yet behaves like wild-type 53BP1 with respect to immunoglobulin class switch recombination (CSR). 53BP18A recruits RIF1 but fails to recruit the DDR protein PTIP to DSBs, and disruption of PTIP phenocopies 53BP18A. We conclude that 53BP1 promotes productive CSR and suppresses mutagenic DNA repair through distinct phosphodependent interactions with RIF1 and PTIP.

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U2 - 10.1016/j.cell.2013.05.023

DO - 10.1016/j.cell.2013.05.023

M3 - Article

C2 - 23727112

AN - SCOPUS:84878893538

SN - 0092-8674

VL - 153

SP - 1266

EP - 1280

JO - Cell

JF - Cell

IS - 6

ER -

53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions

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