Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1.

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.

• Authors: 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, Jordi Surrallés
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 967 (03 06 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 29511213 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BRCA1 Protein
• BRCA1 protein, human
• Carrier Proteins
• DNA-Binding Proteins
• EDC4 protein, human
• Nuclear Proteins
• Proteins
• RNA Caps
• TOPBP1 protein, human
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1

Topics

• BRCA1 Protein (genetics, metabolism)
• Breast Neoplasms (genetics, metabolism)
• Carrier Proteins (genetics, metabolism)
• DNA Repair
• DNA-Binding Proteins (genetics, metabolism)
• Female
• Homologous Recombination
• Humans
• Mutation
• Nuclear Proteins (genetics, metabolism)
• Poly (ADP-Ribose) Polymerase-1 (genetics, metabolism)
• Protein Binding
• Proteins (genetics, metabolism)
• RNA Caps (genetics, metabolism)