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

Jordi Minguillón Pedreño; Massimo Bogliolo; Jordi Surrallés i Calonge; Llorenç Rovirosa Mulet; Pilar Bustamante-Madrid; Cristina Camps-Fajol; Gorka Ruiz de Garibay; Hermela Shimelis; Helena Montanuy Escribano; Roser Pujol; Gonzalo Hernandez; Pau Castillo; Penny Soucy; Griselda Martrat; Antonio Gómez Moruno; Daniel Cuadras; María J García; Javier Gayarre; Conxi Lázaro Garcia; Javier Benitez; Fergus J. Couch; Miquel Ángel Pujana

doi:10.3390/cancers14020353

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

Jordi Minguillón Pedreño, Massimo Bogliolo, Jordi Surrallés i Calonge, Llorenç Rovirosa Mulet, Pilar Bustamante-Madrid, Cristina Camps-Fajol, Gorka Ruiz de Garibay, Hermela Shimelis, Helena Montanuy Escribano, Roser Pujol, Gonzalo Hernandez, Pau Castillo, Penny Soucy, Griselda Martrat, Antonio Gómez Moruno, Daniel Cuadras, María J García, Javier Gayarre, Conxi Lázaro Garcia, Javier BenitezFergus J. Couch, Miquel Ángel Pujana

Departamento de Genética y Microbiología

Producción científica: Contribución a una revista › Artículo › Investigación › revisión exhaustiva

Resumen

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.

Idioma original	Inglés
Publicación	Cancers
Volumen	14
N.º	2
DOI	https://doi.org/10.3390/cancers14020353
Estado	Publicada - 2022

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Minguillón Pedreño, J., Bogliolo, M., Surrallés i Calonge, J., Rovirosa Mulet, L., Bustamante-Madrid, P., Camps-Fajol, C., de Garibay, G. R., Shimelis, H., Montanuy Escribano, H., Pujol, R., Hernandez, G., Castillo, P., Soucy, P., Martrat, G., Gómez Moruno, A., Cuadras, D., García, M. J., Gayarre, J., Lázaro Garcia, C., ... Pujana, M. Á. (2022). CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival. Cancers, 14(2). https://doi.org/10.3390/cancers14020353

@article{327d73272fa3442abeeadda640df41cc,

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.",

keywords = "BRCA2, Breast cancer, CDK5RAP3, DNA repair, Chemoresistance",

author = "{Minguill{\'o}n Pedre{\~n}o}, Jordi and Massimo Bogliolo and {Surrall{\'e}s i Calonge}, Jordi and {Rovirosa Mulet}, Lloren{\c c} and Pilar Bustamante-Madrid and Cristina Camps-Fajol and {de Garibay}, {Gorka Ruiz} and Hermela Shimelis and {Montanuy Escribano}, Helena and Roser Pujol and Gonzalo Hernandez and Pau Castillo and Penny Soucy and Griselda Martrat and {G{\'o}mez Moruno}, Antonio and Daniel Cuadras and Garc{\'i}a, {Mar{\'i}a J} and Javier Gayarre and {L{\'a}zaro Garcia}, Conxi and Javier Benitez and Couch, {Fergus J.} and Pujana, {Miquel {\'A}ngel}",

year = "2022",

doi = "10.3390/cancers14020353",

language = "English",

volume = "14",

journal = "Cancers",

issn = "2072-6694",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "2",

}

Minguillón Pedreño, J, Bogliolo, M , Surrallés i Calonge, J, Rovirosa Mulet, L, Bustamante-Madrid, P, Camps-Fajol, C, de Garibay, GR, Shimelis, H, Montanuy Escribano, H, Pujol, R, Hernandez, G, Castillo, P, Soucy, P, Martrat, G, Gómez Moruno, A, Cuadras, D, García, MJ, Gayarre, J, Lázaro Garcia, C, Benitez, J, Couch, FJ & Pujana, MÁ 2022, 'CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival', Cancers, vol. 14, n.º 2. https://doi.org/10.3390/cancers14020353

TY - JOUR

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

AU - Minguillón Pedreño, Jordi

AU - Bogliolo, Massimo

AU - Surrallés i Calonge, Jordi

AU - Rovirosa Mulet, Llorenç

AU - Bustamante-Madrid, Pilar

AU - Camps-Fajol, Cristina

AU - de Garibay, Gorka Ruiz

AU - Shimelis, Hermela

AU - Montanuy Escribano, Helena

AU - Pujol, Roser

AU - Hernandez, Gonzalo

AU - Castillo, Pau

AU - Soucy, Penny

AU - Martrat, Griselda

AU - Gómez Moruno, Antonio

AU - Cuadras, Daniel

AU - García, María J

AU - Gayarre, Javier

AU - Lázaro Garcia, Conxi

AU - Benitez, Javier

AU - Couch, Fergus J.

AU - Pujana, Miquel Ángel

PY - 2022

Y1 - 2022

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 - DNA repair

KW - Chemoresistance

U2 - 10.3390/cancers14020353

DO - 10.3390/cancers14020353

M3 - Article

C2 - 35053516

SN - 2072-6694

VL - 14

JO - Cancers

JF - Cancers

IS - 2

ER -

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

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