Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1

作者：Hernandez Gonzalo; Jose Ramirez Maria; Minguillon Jordi; Quiles Paco; Ruiz de Garibay Gorka; Aza Carmona Miriam; Bogliolo Massimo; Pujol Roser; Prados Carvajal Rosario; Fernandez Juana; Garcia Nadia; Lopez Adria; Gutierrez Enriquez Sara; Diez Orland; Benitez Javier; Salinas Monica; Teule Alex; Brunet Joan; Radice Paolo; Peterlongo Paolo; Schindler Detlev; Huertas Pablo; Puente Xose S; Lazaro Conxi; Angel Pujana Miquel; Surralles Jordi

来源：Nature Communications, 2018, 9(1): 967.

DOI：10.1038/s41467-018-03433-3

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.

• 出版日期2018-3-6