CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival

Autor: Minguillón, Jordi, Ramírez, María José, Rovirosa, Llorenç, Bustamante Madrid, Pilar, Camps Fajol, Cristina, Ruiz de Garibay, Gorka, Shimelis, Hermela, Montanuy, Helena, Pujol, Roser, Hernandez, Gonzalo, Bogliolo, Massimo, Castillo, Pau, Soucy, Penny, Martrat, Griselda, Gómez, Antonio, Cuadras, Daniel, García, María J., Gayarre, Javier, Lázaro, Conxi, Benítez, Javier, Couch, Fergus J., Pujana, Miquel Angel, Surrallés, Jordi, CIMBA Consortium
Rok vydání: 2022
Předmět:
Zdroj: Dipòsit Digital de la UB
Universidad de Barcelona
Cancers; Volume 14; Issue 2; Pages: 353
Cancers, Vol 14, Iss 353, p 353 (2022)
Dipòsit Digital de Documents de la UAB
Universitat Autònoma de Barcelona
Cancers
r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname
ISSN: 2072-6694
Popis: Simple Summary BRCA2 is an essential gene for DNA repair by homologous recombination and is often mutated in families at risk of breast and ovarian cancer. In this study we identified CDK5RAP3 tumor suppressor as a new BRCA2-interacting protein. CDK5RAP3 negatively regulates DNA repair of double-strand breaks, providing a new mechanism of DNA damage resistance. Consistently, gene expression data analysis showed CDK5RAP3 overexpression in breast cancer is associated with poorer survival. Finally, we identified common genetic variations in the CDK5RAP3 locus as potentially associated with breast and ovarian cancer risk in a large cohort of BRCA1 and BRCA2 mutation carriers. 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.
Databáze: OpenAIRE
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