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 & 6 others Detlev Schindler, Pablo Huertas, Xose S Puente, Conxi Lázaro, Miquel Àngel Pujana, Jordi Surrallés

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)967
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - Mar 6 2018

Fingerprint

DNA Repair
Repair
deoxyribonucleic acid
mutations
cancer
breast
Breast Neoplasms
proteins
ribose
adenosine diphosphate
DNA
inhibitors
Recombinational DNA Repair
Tumors
Neoplasms
Mutation
Proteins
tumors
Germ-Line Mutation
Genomic Instability

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

Cite this

Hernández, G., Ramírez, M. J., Minguillón, J., Quiles, P., Ruiz de Garibay, G., Aza-Carmona, M., ... 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 journalArticle

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 G, Ramírez MJ, Minguillón J, Quiles P, Ruiz de Garibay G, Aza-Carmona M et al. Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1. Nature Communications. 2018 Mar 6;9(1):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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AU - Ramírez, María José

AU - Minguillón, Jordi

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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

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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

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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.

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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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SP - 967

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

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