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Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1.

Gonzalo HernándezMaría José RamírezJordi MinguillónPaco QuilesGorka Ruiz de GaribayMiriam Aza-CarmonaMassimo BoglioloRoser PujolRosario Prados-CarvajalJuana FernándezNadia GarcíaAdrià LópezSara Gutiérrez-EnríquezOrland DiezJavier BenítezMónica SalinasAlex TeuléJoan BrunetPaolo RadicePaolo PeterlongoDetlev SchindlerPablo HuertasXose S PuenteConxi LázaroMiquel Àngel PujanaJordi Surrallés
Published in: Nature communications (2018)
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.
Keyphrases
  • dna repair
  • dna damage
  • breast cancer risk
  • dna damage response
  • gene expression
  • oxidative stress
  • squamous cell carcinoma
  • climate change
  • binding protein
  • circulating tumor
  • circulating tumor cells