Cancers (Jan 2022)
CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival
- 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
Affiliations
- Jordi Minguillón
- 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
- María José Ramírez
- 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
- Llorenç Rovirosa
- 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
- Pilar Bustamante-Madrid
- 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
- Cristina Camps-Fajol
- 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
- Gorka Ruiz de Garibay
- 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
- Hermela Shimelis
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55901, USA
- Helena Montanuy
- 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
- Roser Pujol
- 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
- Gonzalo Hernandez
- 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
- Massimo Bogliolo
- 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
- Pau Castillo
- 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
- Penny Soucy
- Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, QC G1E 6W2, Canada
- Griselda Martrat
- 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
- Antonio Gómez
- Cancer Epigenetics and Biology Program, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, 08908 Barcelona, Spain
- Daniel Cuadras
- 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
- María J. García
- Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
- Javier Gayarre
- Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
- CIMBA
- Conxi Lázaro
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, 08908 Barcelona, Spain
- Javier Benítez
- Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
- Fergus J. Couch
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55901, USA
- Miquel Angel Pujana
- 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
- Jordi Surrallés
- 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
- DOI
- https://doi.org/10.3390/cancers14020353
- Journal volume & issue
-
Vol. 14,
no. 2
p. 353
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.
Keywords