REV7 counteracts DNA double-strand break resection and affects PARP inhibition

Guotai Xu; J. Ross Chapman; Inger Brandsma; Jingsong Yuan; Martin Mistrik; Peter Bouwman; Jirina Bartkova; Ewa Gogola; Daniël Warmerdam; Marco Barazas; Janneke E. Jaspers; Kenji Watanabe; Mark Pieterse; Ariena Kersbergen; Wendy Sol; Patrick H.N. Celie; Philip C. Schouten; Bram Van Den Broek; Ahmed Salman; Marja Nieuwland; Iris De Rink; Jorma De Ronde; Kees Jalink; Simon J. Boulton; Junjie Chen; Dik C. Van Gent; Jiri Bartek; Jos Jonkers; Piet Borst; Sven Rottenberg

doi:10.1038/nature14328

REV7 counteracts DNA double-strand break resection and affects PARP inhibition

Guotai Xu, J. Ross Chapman, Inger Brandsma, Jingsong Yuan, Martin Mistrik, Peter Bouwman, Jirina Bartkova, Ewa Gogola, Daniël Warmerdam, Marco Barazas, Janneke E. Jaspers, Kenji Watanabe, Mark Pieterse, Ariena Kersbergen, Wendy Sol, Patrick H.N. Celie, Philip C. Schouten, Bram Van Den Broek, Ahmed Salman, Marja NieuwlandIris De Rink, Jorma De Ronde, Kees Jalink, Simon J. Boulton, Junjie Chen, Dik C. Van Gent, Jiri Bartek, Jos Jonkers, Piet Borst, Sven Rottenberg

Experimental Radiation Oncology

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

442 Scopus citations

Abstract

Error-free repair of DNA double-strand breaks (DSBs) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway. In the absence of BRCA1-mediated HR, the administration of PARP inhibitors induces synthetic lethality of tumour cells of patients with breast or ovarian cancers. Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration. Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases. In particular, little is known about BRCA1-independent restoration of HR. Here we show that loss of REV7 (also known as MAD2L2) in mouse and human cell lines re-establishes CTIP-dependent end resection of DSBs in BRCA1-deficient cells, leading to HR restoration and PARP inhibitor resistance, which is reversed by ATM kinase inhibition. REV7 is recruited to DSBs in a manner dependent on the H2AX-MDC1-RNF8-RNF168-53BP1 chromatin pathway, and seems to block HR and promote end joining in addition to its regulatory role in DNA damage tolerance. Finally, we establish that REV7 blocks DSB resection to promote non-homologous end-joining during immunoglobulin class switch recombination. Our results reveal an unexpected crucial function of REV7 downstream of 53BP1 in coordinating pathological DSB repair pathway choices in BRCA1-deficient cells.

Original language	English (US)
Pages (from-to)	541-544
Number of pages	4
Journal	Nature
Volume	521
Issue number	7553
DOIs	https://doi.org/10.1038/nature14328
State	Published - May 28 2015

ASJC Scopus subject areas

General

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Cytogenetics and Cell Authentication Core

Access to Document

10.1038/nature14328

Cite this

Xu, G., Ross Chapman, J., Brandsma, I., Yuan, J., Mistrik, M., Bouwman, P., Bartkova, J., Gogola, E., Warmerdam, D., Barazas, M., Jaspers, J. E., Watanabe, K., Pieterse, M., Kersbergen, A., Sol, W., Celie, P. H. N., Schouten, P. C., Van Den Broek, B., Salman, A., ... Rottenberg, S. (2015). REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Nature, 521(7553), 541-544. https://doi.org/10.1038/nature14328

Xu, G, Ross Chapman, J, Brandsma, I, Yuan, J, Mistrik, M, Bouwman, P, Bartkova, J, Gogola, E, Warmerdam, D, Barazas, M, Jaspers, JE, Watanabe, K, Pieterse, M, Kersbergen, A, Sol, W, Celie, PHN, Schouten, PC, Van Den Broek, B, Salman, A, Nieuwland, M, De Rink, I, De Ronde, J, Jalink, K, Boulton, SJ, Chen, J, Van Gent, DC, Bartek, J, Jonkers, J, Borst, P & Rottenberg, S 2015, 'REV7 counteracts DNA double-strand break resection and affects PARP inhibition', Nature, vol. 521, no. 7553, pp. 541-544. https://doi.org/10.1038/nature14328

@article{5304be31f4c84efd9d6e1389b2d9117b,

title = "REV7 counteracts DNA double-strand break resection and affects PARP inhibition",

abstract = "Error-free repair of DNA double-strand breaks (DSBs) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway. In the absence of BRCA1-mediated HR, the administration of PARP inhibitors induces synthetic lethality of tumour cells of patients with breast or ovarian cancers. Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration. Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases. In particular, little is known about BRCA1-independent restoration of HR. Here we show that loss of REV7 (also known as MAD2L2) in mouse and human cell lines re-establishes CTIP-dependent end resection of DSBs in BRCA1-deficient cells, leading to HR restoration and PARP inhibitor resistance, which is reversed by ATM kinase inhibition. REV7 is recruited to DSBs in a manner dependent on the H2AX-MDC1-RNF8-RNF168-53BP1 chromatin pathway, and seems to block HR and promote end joining in addition to its regulatory role in DNA damage tolerance. Finally, we establish that REV7 blocks DSB resection to promote non-homologous end-joining during immunoglobulin class switch recombination. Our results reveal an unexpected crucial function of REV7 downstream of 53BP1 in coordinating pathological DSB repair pathway choices in BRCA1-deficient cells.",

author = "Guotai Xu and {Ross Chapman}, J. and Inger Brandsma and Jingsong Yuan and Martin Mistrik and Peter Bouwman and Jirina Bartkova and Ewa Gogola and Dani{\"e}l Warmerdam and Marco Barazas and Jaspers, {Janneke E.} and Kenji Watanabe and Mark Pieterse and Ariena Kersbergen and Wendy Sol and Celie, {Patrick H.N.} and Schouten, {Philip C.} and {Van Den Broek}, Bram and Ahmed Salman and Marja Nieuwland and {De Rink}, Iris and {De Ronde}, Jorma and Kees Jalink and Boulton, {Simon J.} and Junjie Chen and {Van Gent}, {Dik C.} and Jiri Bartek and Jos Jonkers and Piet Borst and Sven Rottenberg",

year = "2015",

month = may,

day = "28",

doi = "10.1038/nature14328",

language = "English (US)",

volume = "521",

pages = "541--544",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7553",

}

TY - JOUR

T1 - REV7 counteracts DNA double-strand break resection and affects PARP inhibition

AU - Xu, Guotai

AU - Ross Chapman, J.

AU - Brandsma, Inger

AU - Yuan, Jingsong

AU - Mistrik, Martin

AU - Bouwman, Peter

AU - Bartkova, Jirina

AU - Gogola, Ewa

AU - Warmerdam, Daniël

AU - Barazas, Marco

AU - Jaspers, Janneke E.

AU - Watanabe, Kenji

AU - Pieterse, Mark

AU - Kersbergen, Ariena

AU - Sol, Wendy

AU - Celie, Patrick H.N.

AU - Schouten, Philip C.

AU - Van Den Broek, Bram

AU - Salman, Ahmed

AU - Nieuwland, Marja

AU - De Rink, Iris

AU - De Ronde, Jorma

AU - Jalink, Kees

AU - Boulton, Simon J.

AU - Chen, Junjie

AU - Van Gent, Dik C.

AU - Bartek, Jiri

AU - Jonkers, Jos

AU - Borst, Piet

AU - Rottenberg, Sven

PY - 2015/5/28

Y1 - 2015/5/28

N2 - Error-free repair of DNA double-strand breaks (DSBs) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway. In the absence of BRCA1-mediated HR, the administration of PARP inhibitors induces synthetic lethality of tumour cells of patients with breast or ovarian cancers. Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration. Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases. In particular, little is known about BRCA1-independent restoration of HR. Here we show that loss of REV7 (also known as MAD2L2) in mouse and human cell lines re-establishes CTIP-dependent end resection of DSBs in BRCA1-deficient cells, leading to HR restoration and PARP inhibitor resistance, which is reversed by ATM kinase inhibition. REV7 is recruited to DSBs in a manner dependent on the H2AX-MDC1-RNF8-RNF168-53BP1 chromatin pathway, and seems to block HR and promote end joining in addition to its regulatory role in DNA damage tolerance. Finally, we establish that REV7 blocks DSB resection to promote non-homologous end-joining during immunoglobulin class switch recombination. Our results reveal an unexpected crucial function of REV7 downstream of 53BP1 in coordinating pathological DSB repair pathway choices in BRCA1-deficient cells.

AB - Error-free repair of DNA double-strand breaks (DSBs) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway. In the absence of BRCA1-mediated HR, the administration of PARP inhibitors induces synthetic lethality of tumour cells of patients with breast or ovarian cancers. Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration. Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases. In particular, little is known about BRCA1-independent restoration of HR. Here we show that loss of REV7 (also known as MAD2L2) in mouse and human cell lines re-establishes CTIP-dependent end resection of DSBs in BRCA1-deficient cells, leading to HR restoration and PARP inhibitor resistance, which is reversed by ATM kinase inhibition. REV7 is recruited to DSBs in a manner dependent on the H2AX-MDC1-RNF8-RNF168-53BP1 chromatin pathway, and seems to block HR and promote end joining in addition to its regulatory role in DNA damage tolerance. Finally, we establish that REV7 blocks DSB resection to promote non-homologous end-joining during immunoglobulin class switch recombination. Our results reveal an unexpected crucial function of REV7 downstream of 53BP1 in coordinating pathological DSB repair pathway choices in BRCA1-deficient cells.

UR - http://www.scopus.com/inward/record.url?scp=84930678981&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930678981&partnerID=8YFLogxK

U2 - 10.1038/nature14328

DO - 10.1038/nature14328

M3 - Article

C2 - 25799992

AN - SCOPUS:84930678981

SN - 0028-0836

VL - 521

SP - 541

EP - 544

JO - Nature

JF - Nature

IS - 7553

ER -

REV7 counteracts DNA double-strand break resection and affects PARP inhibition

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

Access to Document

Other files and links

Fingerprint

Cite this