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Nat Commun. 2018 Mar 6;9(1):967. doi: 10.1038/s41467-018-03433-3.

Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1.

Author information

1
Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Bellaterra, 08193, Spain.
2
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, 08193, Spain.
3
Hereditary Cancer Programme, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, 08908, Spain.
4
Breast Cancer and Systems Biology Laboratory, Program Against Cancer Therapeutic Resistance (ProCURE), ICO, IDIBELL, L'Hospitalet del Llobregat, Barcelona, 08908, Spain.
5
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER) and Departamento de Genética, Universidad de Sevilla, Sevilla, 41080, Spain.
6
Hereditary Cancer Programme, ICO, Girona Biomedical Research Institute (IDIBGI), Girona, 17007, Spain.
7
Oncogenetics Group, Vall d´Hebron Institute of Oncology (VHIO), Barcelona, 08035, Spain.
8
Area of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Barcelona, 08035, Spain.
9
Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, 28029, Spain.
10
Department of Preventive and Predictive Medicine, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, 20133, Italy.
11
Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, IFOM, Fondazione Istituto FIRC di Oncologia Molecolare and Unit of Molecular Bases of Genetic Risk and Genetic Testing, Milan, 20139, Italy.
12
Department of Human Genetics, Wurzburg University, Wurzburg, 97070, Germany.
13
Department of Biochemistry and Molecular Biology, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, 33006, Spain.
14
Breast Cancer and Systems Biology Laboratory, Program Against Cancer Therapeutic Resistance (ProCURE), ICO, IDIBELL, L'Hospitalet del Llobregat, Barcelona, 08908, Spain. mapujana@iconcologia.net.
15
Centro de Investigación Biomédica en Red de Oncología (CIBERONC), Oviedo, 33006, Spain. mapujana@iconcologia.net.
16
Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Bellaterra, 08193, Spain. jsurralles@santpau.cat.
17
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, 08193, Spain. jsurralles@santpau.cat.
18
Department of Genetics and Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Barcelona, 08028, Spain. jsurralles@santpau.cat.

Abstract

BRCA1 is a tumor suppressor that regulates DNA repair by homologous recombination. Germline mutations in BRCA1 are associated with increased risk of breast and ovarian cancer and BRCA1 deficient tumors are exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Therefore, uncovering additional components of this DNA repair pathway is of extreme importance for further understanding cancer development and therapeutic vulnerabilities. Here, we identify EDC4, a known component of processing-bodies and regulator of mRNA decapping, as a member of the BRCA1-BRIP1-TOPBP1 complex. EDC4 plays a key role in homologous recombination by stimulating end resection at double-strand breaks. EDC4 deficiency leads to genome instability and hypersensitivity to DNA interstrand cross-linking drugs and PARP inhibitors. Lack-of-function mutations in EDC4 were detected in BRCA1/2-mutation-negative breast cancer cases, suggesting a role in breast cancer susceptibility. Collectively, this study recognizes EDC4 with a dual role in decapping and DNA repair whose inactivation phenocopies BRCA1 deficiency.

PMID:
29511213
PMCID:
PMC5840268
DOI:
10.1038/s41467-018-03433-3
[Indexed for MEDLINE]
Free PMC Article

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