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

E. Callen; N. Wong; H.-T. Chen; R.B. Faryabi; F. Polato; Margarida  Santos; A. Nussenzweig; M.J. Kruhlak; M. Di Virgilio; M.C. Nussenzweig; M. Nieto-Soler; O. Fernandez-Capetillo; L.M. Starnes; J.A. Daniel; D.R. Wesemann; F.W. Alt; J.-E. Lee; K. Ge; A. Tubbs; B.P. Sleckman

doi:10.1016/j.cell.2013.05.023

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

E. Callen, N. Wong, H.-T. Chen, R.B. Faryabi, F. Polato, Margarida Santos, A. Nussenzweig, M.J. Kruhlak, M. Di Virgilio, M.C. Nussenzweig, M. Nieto-Soler, O. Fernandez-Capetillo, L.M. Starnes, J.A. Daniel, D.R. Wesemann, F.W. Alt, J.-E. Lee, K. Ge, A. Tubbs, B.P. Sleckman

Novo Nordisk Foundation Center for Protein Research

216 Citations (Scopus)

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
Journal	Cell
Volume	153
Issue number	6
Pages (from-to)	1266-1280
Number of pages	15
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2013.05.023
Publication status	Published - 6 Jun 2013

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Callen, E., Wong, N., Chen, H-T., Faryabi, R. B., Polato, F., Santos, M., Nussenzweig, A., Kruhlak, M. J., Di Virgilio, M., Nussenzweig, M. C., Nieto-Soler, M., Fernandez-Capetillo, O., Starnes, L. M., Daniel, J. A., Wesemann, D. R., Alt, F. W., Lee, J-E., Ge, K., Tubbs, A., & Sleckman, B. P. (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, Wong, N, Chen, H-T, Faryabi, RB, Polato, F, Santos, M, Nussenzweig, A, Kruhlak, MJ, Di Virgilio, M, Nussenzweig, MC, Nieto-Soler, M, Fernandez-Capetillo, O, Starnes, LM, Daniel, JA, Wesemann, DR, Alt, FW, Lee, J-E, Ge, K, Tubbs, A & Sleckman, BP 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

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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 = "E. Callen and N. Wong and H.-T. Chen and R.B. Faryabi and F. Polato and Margarida Santos and A. Nussenzweig and M.J. Kruhlak and {Di Virgilio}, M. and M.C. Nussenzweig and M. Nieto-Soler and O. Fernandez-Capetillo and L.M. Starnes and J.A. Daniel and D.R. Wesemann and F.W. Alt and J.-E. Lee and K. Ge and A. Tubbs and B.P. Sleckman",

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

language = "English",

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

AU - Callen, E.

AU - Wong, N.

AU - Chen, H.-T.

AU - Faryabi, R.B.

AU - Polato, F.

AU - Santos, Margarida

AU - Nussenzweig, A.

AU - Kruhlak, M.J.

AU - Di Virgilio, M.

AU - Nussenzweig, M.C.

AU - Nieto-Soler, M.

AU - Fernandez-Capetillo, O.

AU - Starnes, L.M.

AU - Daniel, J.A.

AU - Wesemann, D.R.

AU - Alt, F.W.

AU - Lee, J.-E.

AU - Ge, K.

AU - Tubbs, A.

AU - Sleckman, B.P.

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

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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

Abstract

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