Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1

Gonzalo Hernández; María José Ramírez; Jordi Minguillón; Paco Quiles; Gorka Ruiz de Garibay; Miriam Aza-Carmona; Massimo Bogliolo; Roser Pujol; Rosario Prados-Carvajal; Juana Fernández; Nadia García; Adrià López; Sara Gutiérrez-Enríquez; Orland Diez; Javier Benítez; Mónica Salinas; Alex Teulé; Joan Brunet; Paolo Radice; Paolo Peterlongo; Detlev Schindler; Pablo Huertas; Xose S Puente; Conxi Lázaro; Miquel Àngel Pujana; Jordi Surrallés

doi:10.1038/s41467-018-03433-3

Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1

Gonzalo Hernández, María José Ramírez, Jordi Minguillón, Paco Quiles, Gorka Ruiz de Garibay, Miriam Aza-Carmona, Massimo Bogliolo, Roser Pujol, Rosario Prados-Carvajal, Juana Fernández, Nadia García, Adrià López, Sara Gutiérrez-Enríquez, Orland Diez, Javier Benítez, Mónica Salinas, Alex Teulé, Joan Brunet, Paolo Radice, Paolo PeterlongoDetlev Schindler, Pablo Huertas, Xose S Puente, Conxi Lázaro, Miquel Àngel Pujana, Jordi Surrallés

Fondazione IRCCS Istituto Nazionale dei Tumori

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

Abstract

BRCA1 is a tumor suppressor that regulates DNA repair by homologous recombination. Germline mutations in BRCA1 are associated with increased risk of breast and ovarian cancer and BRCA1 deficient tumors are exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Therefore, uncovering additional components of this DNA repair pathway is of extreme importance for further understanding cancer development and therapeutic vulnerabilities. Here, we identify EDC4, a known component of processing-bodies and regulator of mRNA decapping, as a member of the BRCA1-BRIP1-TOPBP1 complex. EDC4 plays a key role in homologous recombination by stimulating end resection at double-strand breaks. EDC4 deficiency leads to genome instability and hypersensitivity to DNA interstrand cross-linking drugs and PARP inhibitors. Lack-of-function mutations in EDC4 were detected in BRCA1/2-mutation-negative breast cancer cases, suggesting a role in breast cancer susceptibility. Collectively, this study recognizes EDC4 with a dual role in decapping and DNA repair whose inactivation phenocopies BRCA1 deficiency.

Original language	English
Pages (from-to)	967
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-03433-3
Publication status	Published - Mar 6 2018

Keywords

BRCA1 Protein/genetics
Breast Neoplasms/genetics
Carrier Proteins/genetics
DNA Repair
DNA-Binding Proteins/genetics
Female
Homologous Recombination
Humans
Mutation
Nuclear Proteins/genetics
Poly (ADP-Ribose) Polymerase-1/genetics
Protein Binding
Proteins/genetics
RNA Caps/genetics

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Hernández, G., Ramírez, M. J., Minguillón, J., Quiles, P., Ruiz de Garibay, G., Aza-Carmona, M., Bogliolo, M., Pujol, R., Prados-Carvajal, R., Fernández, J., García, N., López, A., Gutiérrez-Enríquez, S., Diez, O., Benítez, J., Salinas, M., Teulé, A., Brunet, J., Radice, P., ... Surrallés, J. (2018). Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1. Nature Communications, 9(1), 967. https://doi.org/10.1038/s41467-018-03433-3

Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1. / Hernández, Gonzalo; Ramírez, María José; Minguillón, Jordi; Quiles, Paco; Ruiz de Garibay, Gorka; Aza-Carmona, Miriam; Bogliolo, Massimo; Pujol, Roser; Prados-Carvajal, Rosario; Fernández, Juana; García, Nadia; López, Adrià; Gutiérrez-Enríquez, Sara; Diez, Orland; Benítez, Javier; Salinas, Mónica; Teulé, Alex; Brunet, Joan; Radice, Paolo; Peterlongo, Paolo; Schindler, Detlev; Huertas, Pablo; Puente, Xose S; Lázaro, Conxi; Pujana, Miquel Àngel; Surrallés, Jordi.

In: Nature Communications, Vol. 9, No. 1, 06.03.2018, p. 967.

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

Hernández, G, Ramírez, MJ, Minguillón, J, Quiles, P, Ruiz de Garibay, G, Aza-Carmona, M, Bogliolo, M, Pujol, R, Prados-Carvajal, R, Fernández, J, García, N, López, A, Gutiérrez-Enríquez, S, Diez, O, Benítez, J, Salinas, M, Teulé, A, Brunet, J, Radice, P, Peterlongo, P, Schindler, D, Huertas, P, Puente, XS, Lázaro, C, Pujana, MÀ & Surrallés, J 2018, 'Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1', Nature Communications, vol. 9, no. 1, pp. 967. https://doi.org/10.1038/s41467-018-03433-3

Hernández, Gonzalo ; Ramírez, María José ; Minguillón, Jordi ; Quiles, Paco ; Ruiz de Garibay, Gorka ; Aza-Carmona, Miriam ; Bogliolo, Massimo ; Pujol, Roser ; Prados-Carvajal, Rosario ; Fernández, Juana ; García, Nadia ; López, Adrià ; Gutiérrez-Enríquez, Sara ; Diez, Orland ; Benítez, Javier ; Salinas, Mónica ; Teulé, Alex ; Brunet, Joan ; Radice, Paolo ; Peterlongo, Paolo ; Schindler, Detlev ; Huertas, Pablo ; Puente, Xose S ; Lázaro, Conxi ; Pujana, Miquel Àngel ; Surrallés, Jordi. / Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1. In: Nature Communications. 2018 ; Vol. 9, No. 1. pp. 967.

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abstract = "BRCA1 is a tumor suppressor that regulates DNA repair by homologous recombination. Germline mutations in BRCA1 are associated with increased risk of breast and ovarian cancer and BRCA1 deficient tumors are exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Therefore, uncovering additional components of this DNA repair pathway is of extreme importance for further understanding cancer development and therapeutic vulnerabilities. Here, we identify EDC4, a known component of processing-bodies and regulator of mRNA decapping, as a member of the BRCA1-BRIP1-TOPBP1 complex. EDC4 plays a key role in homologous recombination by stimulating end resection at double-strand breaks. EDC4 deficiency leads to genome instability and hypersensitivity to DNA interstrand cross-linking drugs and PARP inhibitors. Lack-of-function mutations in EDC4 were detected in BRCA1/2-mutation-negative breast cancer cases, suggesting a role in breast cancer susceptibility. Collectively, this study recognizes EDC4 with a dual role in decapping and DNA repair whose inactivation phenocopies BRCA1 deficiency.",

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AU - Hernández, Gonzalo

AU - Ramírez, María José

AU - Minguillón, Jordi

AU - Quiles, Paco

AU - Ruiz de Garibay, Gorka

AU - Aza-Carmona, Miriam

AU - Bogliolo, Massimo

AU - Pujol, Roser

AU - Prados-Carvajal, Rosario

AU - Fernández, Juana

AU - García, Nadia

AU - López, Adrià

AU - Gutiérrez-Enríquez, Sara

AU - Diez, Orland

AU - Benítez, Javier

AU - Salinas, Mónica

AU - Teulé, Alex

AU - Brunet, Joan

AU - Radice, Paolo

AU - Peterlongo, Paolo

AU - Schindler, Detlev

AU - Huertas, Pablo

AU - Puente, Xose S

AU - Lázaro, Conxi

AU - Pujana, Miquel Àngel

AU - Surrallés, Jordi

PY - 2018/3/6

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N2 - BRCA1 is a tumor suppressor that regulates DNA repair by homologous recombination. Germline mutations in BRCA1 are associated with increased risk of breast and ovarian cancer and BRCA1 deficient tumors are exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Therefore, uncovering additional components of this DNA repair pathway is of extreme importance for further understanding cancer development and therapeutic vulnerabilities. Here, we identify EDC4, a known component of processing-bodies and regulator of mRNA decapping, as a member of the BRCA1-BRIP1-TOPBP1 complex. EDC4 plays a key role in homologous recombination by stimulating end resection at double-strand breaks. EDC4 deficiency leads to genome instability and hypersensitivity to DNA interstrand cross-linking drugs and PARP inhibitors. Lack-of-function mutations in EDC4 were detected in BRCA1/2-mutation-negative breast cancer cases, suggesting a role in breast cancer susceptibility. Collectively, this study recognizes EDC4 with a dual role in decapping and DNA repair whose inactivation phenocopies BRCA1 deficiency.

AB - BRCA1 is a tumor suppressor that regulates DNA repair by homologous recombination. Germline mutations in BRCA1 are associated with increased risk of breast and ovarian cancer and BRCA1 deficient tumors are exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Therefore, uncovering additional components of this DNA repair pathway is of extreme importance for further understanding cancer development and therapeutic vulnerabilities. Here, we identify EDC4, a known component of processing-bodies and regulator of mRNA decapping, as a member of the BRCA1-BRIP1-TOPBP1 complex. EDC4 plays a key role in homologous recombination by stimulating end resection at double-strand breaks. EDC4 deficiency leads to genome instability and hypersensitivity to DNA interstrand cross-linking drugs and PARP inhibitors. Lack-of-function mutations in EDC4 were detected in BRCA1/2-mutation-negative breast cancer cases, suggesting a role in breast cancer susceptibility. Collectively, this study recognizes EDC4 with a dual role in decapping and DNA repair whose inactivation phenocopies BRCA1 deficiency.

KW - BRCA1 Protein/genetics

KW - Breast Neoplasms/genetics

KW - Carrier Proteins/genetics

KW - DNA Repair

KW - DNA-Binding Proteins/genetics

KW - Female

KW - Homologous Recombination

KW - Humans

KW - Mutation

KW - Nuclear Proteins/genetics

KW - Poly (ADP-Ribose) Polymerase-1/genetics

KW - Protein Binding

KW - Proteins/genetics

KW - RNA Caps/genetics

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DO - 10.1038/s41467-018-03433-3

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