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Title: CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival
Author: Minguillón, Jordi
Ramírez, María José
Rovirosa, Llorenç
Bustamante Madrid, Pilar
Camps i 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
Keywords: Càncer de mama
Breast cancer
Issue Date: 12-Jan-2022
Publisher: MDPI AG
Abstract: 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. 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.
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It is part of: Cancers, 2022, vol 14, num 2
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ISSN: 2072-6694
Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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