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; Conxi Lázaro; Javier Benítez; Fergus J. Couch; Miquel Angel Pujana; Jordi Surrallés

doi:10.3390/cancers14020353

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, Conxi Lázaro, Javier BenítezFergus J. Couch, Miquel Angel Pujana, Jordi Surrallés

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	353
Journal	Cancers
Volume	14
Issue number	2
DOIs	https://doi.org/10.3390/cancers14020353
State	Published - Jan 1 2022

Keywords

BRCA2
Breast cancer
CDK5RAP3
Chemoresistance
DNA repair

ASJC Scopus subject areas

Oncology
Cancer Research

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10.3390/cancers14020353

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Minguillón, J., Ramírez, M. J., Rovirosa, L., Bustamante-Madrid, P., Camps-Fajol, C., De Garibay, G. R., 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., Lázaro, C., ... Surrallés, J. (2022). CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival. Cancers, 14(2), Article 353. https://doi.org/10.3390/cancers14020353

Minguillón, J, Ramírez, MJ, Rovirosa, L, Bustamante-Madrid, P, Camps-Fajol, C, De Garibay, GR, Shimelis, H, Montanuy, H, Pujol, R, Hernandez, G, Bogliolo, M, Castillo, P, Soucy, P, Martrat, G, Gómez, A, Cuadras, D, García, MJ, Gayarre, J, Lázaro, C, Benítez, J, Couch, FJ, Angel Pujana, M & Surrallés, J 2022, 'CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival', Cancers, vol. 14, no. 2, 353. https://doi.org/10.3390/cancers14020353

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

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.",

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T1 - CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival

AU - Minguillón, Jordi

AU - Ramírez, María José

AU - Rovirosa, Llorenç

AU - Bustamante-Madrid, Pilar

AU - Camps-Fajol, Cristina

AU - De Garibay, Gorka Ruiz

AU - Shimelis, Hermela

AU - Montanuy, Helena

AU - Pujol, Roser

AU - Hernandez, Gonzalo

AU - Bogliolo, Massimo

AU - Castillo, Pau

AU - Soucy, Penny

AU - Martrat, Griselda

AU - Gómez, Antonio

AU - Cuadras, Daniel

AU - García, María J.

AU - Gayarre, Javier

AU - Lázaro, Conxi

AU - Benítez, Javier

AU - Couch, Fergus J.

AU - Angel Pujana, Miquel

AU - Surrallés, Jordi

PY - 2022/1/1

Y1 - 2022/1/1

N2 - 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.

AB - 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.

KW - BRCA2

KW - Breast cancer

KW - CDK5RAP3

KW - Chemoresistance

KW - DNA repair

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ER -

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

Abstract

Keywords

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