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Article

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

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Genomic Instability Syndromes and DNA Repair Group and Join Research Unit on Genomic Medicine UAB-Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain
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Center for Biomedical Network Research on Rare Diseases (CIBERER) U-745, 08041 Barcelona, Spain
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Program against Cancer Therapeutic Resistance (ProCURE), Breast Cancer and Systems Biology, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, 08908 Barcelona, Spain
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Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55901, USA
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Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55901, USA
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Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, QC G1E 6W2, Canada
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Cancer Epigenetics and Biology Program, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, 08908 Barcelona, Spain
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Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
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Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, 08908 Barcelona, Spain
*
Authors to whom correspondence should be addressed.
Current address: Computational Oncology Group, Structural Biology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
Consortium of Investigators of Modifiers of BRCA1/2. Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
Academic Editor: Obul Reddy Bandapalli
Cancers 2022, 14(2), 353; https://doi.org/10.3390/cancers14020353
Received: 27 September 2021 / Revised: 27 October 2021 / Accepted: 30 October 2021 / Published: 12 January 2022
(This article belongs to the Special Issue Functional Genomics of Cancer)
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. View Full-Text
Keywords: BRCA2; breast cancer; CDK5RAP3; DNA repair; chemoresistance BRCA2; breast cancer; CDK5RAP3; DNA repair; chemoresistance
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MDPI and ACS Style

Minguillón, J.; Ramírez, M.J.; Rovirosa, L.; Bustamante-Madrid, P.; Camps-Fajol, C.; Ruiz de Garibay, G.; Shimelis, H.; Montanuy, H.; Pujol, R.; Hernandez, G.; Bogliolo, M.; Castillo, P.; Soucy, P.; Martrat, G.; Gómez, A.; Cuadras, D.; García, M.J.; Gayarre, J.; CIMBA; Lázaro, C.; Benítez, J.; Couch, F.J.; Pujana, M.A.; Surrallés, J. CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival. Cancers 2022, 14, 353. https://doi.org/10.3390/cancers14020353

AMA Style

Minguillón J, Ramírez MJ, Rovirosa L, Bustamante-Madrid P, Camps-Fajol C, Ruiz de Garibay G, Shimelis H, Montanuy H, Pujol R, Hernandez G, Bogliolo M, Castillo P, Soucy P, Martrat G, Gómez A, Cuadras D, García MJ, Gayarre J, CIMBA, Lázaro C, Benítez J, Couch FJ, Pujana MA, Surrallés J. CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival. Cancers. 2022; 14(2):353. https://doi.org/10.3390/cancers14020353

Chicago/Turabian Style

Minguillón, Jordi, María J. 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 A. Pujana, and Jordi Surrallés. 2022. "CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival" Cancers 14, no. 2: 353. https://doi.org/10.3390/cancers14020353

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