Publication Date:
2015-03-25
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671316/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671316/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Guotai -- Chapman, J Ross -- Brandsma, Inger -- Yuan, Jingsong -- Mistrik, Martin -- Bouwman, Peter -- Bartkova, Jirina -- Gogola, Ewa -- Warmerdam, Daniel -- Barazas, Marco -- Jaspers, Janneke E -- Watanabe, Kenji -- Pieterse, Mark -- Kersbergen, Ariena -- Sol, Wendy -- Celie, Patrick H N -- Schouten, Philip C -- van den Broek, Bram -- Salman, Ahmed -- Nieuwland, Marja -- de Rink, Iris -- de Ronde, Jorma -- Jalink, Kees -- Boulton, Simon J -- Chen, Junjie -- van Gent, Dik C -- Bartek, Jiri -- Jonkers, Jos -- Borst, Piet -- Rottenberg, Sven -- 090532/Wellcome Trust/United Kingdom -- 104558/Wellcome Trust/United Kingdom -- P30 CA016672/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2015 May 28;521(7553):541-4. doi: 10.1038/nature14328. Epub 2015 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. ; The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK. ; Department of Genetics, Erasmus, University Medical Center, 3000 CA Rotterdam, The Netherlands. ; Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 779 00 Olomouc, Czech Republic. ; Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. ; Danish Cancer Society Research Center, 2100 Copenhagen, Denmark. ; Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. ; Protein Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. ; Deep Sequencing Core Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. ; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. ; DNA Damage Response Laboratory, London Research Institute, Cancer Research UK, Clare Hall, South Mimms, Hertfordshire EN6 3LD, UK. ; 1] Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 779 00 Olomouc, Czech Republic [2] Danish Cancer Society Research Center, 2100 Copenhagen, Denmark. ; 1] Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands [2] Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Laengassstrasse 122, 3012 Bern, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25799992" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors/metabolism
;
BRCA1 Protein/deficiency/genetics/metabolism
;
Cell Line
;
Chromatin/metabolism
;
Chromosomal Proteins, Non-Histone/metabolism
;
*DNA Breaks, Double-Stranded
;
DNA-Binding Proteins/metabolism
;
Drug Resistance, Neoplasm/genetics
;
Histones/metabolism
;
Humans
;
Immunoglobulin Class Switching/genetics
;
Intracellular Signaling Peptides and Proteins/metabolism
;
Mad2 Proteins/deficiency/genetics/*metabolism
;
Mice
;
Nuclear Proteins/metabolism
;
*Poly(ADP-ribose) Polymerase Inhibitors
;
*Recombinational DNA Repair
;
Trans-Activators/metabolism
;
Ubiquitin-Protein Ligases/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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