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 | |
| Publication status | Published - Mar 6 2018 |
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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
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
}
TY - JOUR
T1 - Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1
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
Y1 - 2018/3/6
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
U2 - 10.1038/s41467-018-03433-3
DO - 10.1038/s41467-018-03433-3
M3 - Article
VL - 9
SP - 967
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
ER -