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

The NNF Center for Protein Research

216 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Cell
Vol/bind	153
Udgave nummer	6
Sider (fra-til)	1266-1280
Antal sider	15
ISSN	0092-8674
DOI	https://doi.org/10.1016/j.cell.2013.05.023
Status	Udgivet - 6 jun. 2013

Adgang til dokumentet

10.1016/j.cell.2013.05.023

Andre filer og links

Link to publication in Scopus

Citationsformater

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, bind 153, nr. 6, s. 1266-1280. https://doi.org/10.1016/j.cell.2013.05.023

@article{f80e2b75ae5e4e7781841168ade18fb1,

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",

year = "2013",

month = jun,

day = "6",

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

language = "English",

volume = "153",

pages = "1266--1280",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

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.

UR - http://www.scopus.com/inward/record.url?scp=84878893538&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2013.05.023

DO - 10.1016/j.cell.2013.05.023

M3 - Journal 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

Abstract

Adgang til dokumentet

Andre filer og links

Fingeraftryk

Citationsformater