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Nature. 2015 May 28;521(7553):541-544. doi: 10.1038/nature14328. Epub 2015 Mar 23.

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

Author information

1
Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
2
The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, United Kingdom.
3
Department of Genetics, Erasmus, University Medical Center, Rotterdam, The Netherlands.
4
Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
5
Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
6
Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
7
Danish Cancer Society Research Center, Copenhagen, Denmark.
8
Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
9
Protein Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
10
Deep Sequencing Core Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
11
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
12
DNA Damage Response Laboratory, London Research Institute, Cancer Research UK, Clare Hall, South Mimms EN6 3LD, UK.
13
Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Laengassstrasse 122, 3012 Bern, Switzerland.
#
Contributed equally

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.

PMID:
25799992
PMCID:
PMC4671316
DOI:
10.1038/nature14328
[Indexed for MEDLINE]
Free PMC Article

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