Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1

Gonzalo Hernández, María José Ramírez, Jordi Minguillón, Paco Quiles, Gorka Ruiz de Garibay, Miriam Aza-Carmona, Massimo Bogliolo, Roser Pujol, Rosario Prados-Carvajal, Juana Fernández, Nadia García, Adrià López, Sara Gutiérrez-Enríquez, Orland Diez, Javier Benítez, Mónica Salinas, Alex Teulé, Joan Brunet, Paolo Radice, Paolo Peterlongo, Detlev Schindler, Pablo Huertas, Xose S Puente, Conxi Lázaro, Miquel Àngel Pujana () and Jordi Surrallés ()
Additional contact information
Gonzalo Hernández: Universitat Autònoma de Barcelona
María José Ramírez: Universitat Autònoma de Barcelona
Jordi Minguillón: Universitat Autònoma de Barcelona
Paco Quiles: L’Hospitalet del Llobregat
Gorka Ruiz de Garibay: L’Hospitalet del Llobregat
Miriam Aza-Carmona: Universitat Autònoma de Barcelona
Massimo Bogliolo: Universitat Autònoma de Barcelona
Roser Pujol: Universitat Autònoma de Barcelona
Rosario Prados-Carvajal: Universidad de Sevilla
Juana Fernández: L’Hospitalet del Llobregat
Nadia García: L’Hospitalet del Llobregat
Adrià López: Girona Biomedical Research Institute (IDIBGI)
Sara Gutiérrez-Enríquez: Oncogenetics Group, Vall d´Hebron Institute of Oncology (VHIO)
Orland Diez: Oncogenetics Group, Vall d´Hebron Institute of Oncology (VHIO)
Javier Benítez: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)
Mónica Salinas: L’Hospitalet del Llobregat
Alex Teulé: L’Hospitalet del Llobregat
Joan Brunet: L’Hospitalet del Llobregat
Paolo Radice: 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)
Paolo Peterlongo: Fondazione Istituto FIRC di Oncologia Molecolare and Unit of Molecular Bases of Genetic Risk and Genetic Testing
Detlev Schindler: Wurzburg University
Pablo Huertas: Universidad de Sevilla
Xose S Puente: Universidad de Oviedo
Conxi Lázaro: L’Hospitalet del Llobregat
Miquel Àngel Pujana: L’Hospitalet del Llobregat
Jordi Surrallés: Universitat Autònoma de Barcelona

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03433-3

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