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.
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors: Guotai
authors: G
authors: Xu
authors: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, United Kingdom.
authors: J Ross
authors: JR
authors: Chapman
authors: Department of Genetics, Erasmus, University Medical Center, Rotterdam, The Netherlands.
authors: Inger
authors: I
authors: Brandsma
authors: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Jingsong
authors: J
authors: Yuan
authors: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors: Martin
authors: M
authors: Mistrik
authors: Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors: Peter
authors: P
authors: Bouwman
authors: Danish Cancer Society Research Center, Copenhagen, Denmark.
authors: Jirina
authors: J
authors: Bartkova
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors: Ewa
authors: E
authors: Gogola
authors: Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors: Daniël
authors: D
authors: Warmerdam
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors: Marco
authors: M
authors: Barazas
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors: Janneke E
authors: JE
authors: Jaspers
authors: Danish Cancer Society Research Center, Copenhagen, Denmark.
authors: Kenji
authors: K
authors: Watanabe
authors: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Mark
authors: M
authors: Pieterse
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors: Ariena
authors: A
authors: Kersbergen
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors: Wendy
authors: W
authors: Sol
authors: Protein Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors: Patrick H N
authors: PHN
authors: Celie
authors: Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors: Philip C
authors: PC
authors: Schouten
authors: Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors: Bram
authors: B
authors: van den Broek
authors: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, United Kingdom.
authors: Ahmed
authors: A
authors: Salman
authors: Deep Sequencing Core Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors: Marja
authors: M
authors: Nieuwland
authors: Deep Sequencing Core Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors: Iris
authors: I
authors: de Rink
authors: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors: Jorma
authors: J
authors: de Ronde
authors: Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors: Kees
authors: K
authors: Jalink
authors: DNA Damage Response Laboratory, London Research Institute, Cancer Research UK, Clare Hall, South Mimms EN6 3LD, UK.
authors: Simon J
authors: SJ
authors: Boulton
authors: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Junjie
authors: J
authors: Chen
authors: Department of Genetics, Erasmus, University Medical Center, Rotterdam, The Netherlands.
authors: Dik C
authors: DC
authors: van Gent
authors: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.|Danish Cancer Society Research Center, Copenhagen, Denmark.
authors: Jiri
authors: J
authors: Bartek
authors: Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors: Jos
authors: J
authors: Jonkers
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors: Piet
authors: P
authors: Borst
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.|Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Laengassstrasse 122, 3012 Bern, Switzerland.
authors: Sven
authors: S
authors: Rottenberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D064246:Mad2 Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D059767:Recombinational DNA Repair; D015534:Trans-Activators / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C120552:MAD2L2 protein, human; C413163:MDC1 protein, human; D064246:Mad2 Proteins; C577699:Mad2l2 protein, mouse; D009687:Nuclear Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C486521:RNF8 protein, human; C498301:TP53BP1 protein, human; D015534:Trans-Activators; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; C535210:RNF168 protein, human; D044767:Ubiquitin-Protein Ligases; D064007:Ataxia Telangiectasia Mutated Proteins