학술논문
CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival
Document Type
article
Author
Jordi Minguillón; María José Ramírez; Llorenç Rovirosa; Pilar Bustamante-Madrid; Cristina Camps-Fajol; Gorka Ruiz de Garibay; Hermela Shimelis; Helena Montanuy; Roser Pujol; Gonzalo Hernandez; Massimo Bogliolo; Pau Castillo; Penny Soucy; Griselda Martrat; Antonio Gómez; Daniel Cuadras; María J. García; Javier Gayarre; CIMBA; Conxi Lázaro; Javier Benítez; Fergus J. Couch; Miquel Angel Pujana; Jordi Surrallés
Source
Cancers, Vol 14, Iss 2, p 353 (2022)
Subject
Language
English
ISSN
2072-6694
Abstract
BRCA2 is essential for homologous recombination DNA repair. BRCA2 mutations lead to genome instability and increased risk of breast and ovarian cancer. Similarly, mutations in BRCA2-interacting proteins are also known to modulate sensitivity to DNA damage agents and are established cancer risk factors. Here we identify the tumor suppressor CDK5RAP3 as a novel BRCA2 helical domain-interacting protein. CDK5RAP3 depletion induced DNA damage resistance, homologous recombination and single-strand annealing upregulation, and reduced spontaneous and DNA damage-induced genomic instability, suggesting that CDK5RAP3 negatively regulates double-strand break repair in the S-phase. Consistent with this cellular phenotype, analysis of transcriptomic data revealed an association between low CDK5RAP3 tumor expression and poor survival of breast cancer patients. Finally, we identified common genetic variations in the CDK5RAP3 locus as potentially associated with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Our results uncover CDK5RAP3 as a critical player in DNA repair and breast cancer outcomes.