Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1

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...

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Detalles Bibliográficos
Autores: Hernández Viedma, Gonzalo|||0000-0002-3048-9607, Ramírez de Haro, Ma. José|||0000-0003-1417-7731, Minguillón Pedreño, Jordi|||0000-0003-2124-8294, Quiles, Francisco, Ruiz de Garibay, G., Aza-Carmona, Miriam|||0000-0003-4448-9541, Bogliolo, Massimo|||0000-0001-8240-7784, Pujol Calvet, Maria Roser|||0000-0003-1840-5455, Prados-Carvajal, Rosario, Fernández-Rodríguez, Juana, García, Nadia, López, Adrià, Gutiérrez-Enríquez, Sara|||0000-0002-1711-6101, Diez, Orland|||0000-0001-7339-0570, Benitez, Javier|||0000-0002-0923-7202, Salinas, Monica, Teule, Alex|||0000-0003-0028-7200, Brunet, Joan|||0000-0003-1945-3512, Radice, Paolo|||0000-0001-6298-4111, Peterlongo, Paolo|||0000-0001-6951-6855, Schindler, Detlev, Huertas, Pablo, Puente, Xose P., Lázaro, Coxi, Pujana, Miguel Angel|||0000-0003-3222-4044, Surralles, Jordi|||0000-0002-4041-7519
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:188030
Acceso en línea:https://ddd.uab.cat/record/188030
https://dx.doi.org/urn:doi:10.1038/s41467-018-03433-3
Access Level:acceso abierto
Palabra clave:Cancer
Double-strand DNA breaks
Genomic instability
RNA metabolism
Descripción
Sumario: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.

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