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.
Highlights
BRCA1 is a tumor suppressor that regulates DNA repair by homologous recombination
EDC4 interacts with TOPBP1 and associates with BRCA1
To uncover novel proteins potentially involved in DNA repair and cancer predisposition, we screened for TOPBP1 interactors using the yeast two-hybrid system
Summary
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. Genes involved in homologous recombination (HR) repair pathway such as BRCA1, BRCA2, and PALB2 are an important example. Mutations in these genes cause familial breast cancer and the cancer-prone disease Fanconi anemia (FA) in monoallelic and biallelic carriers, respectively[3]. We observe that EDC4, besides its known role in processing-bodies (P-bodies), interacts with BRCA1 and is involved in HR-mediated DNA repair by regulating its end-resection step and that germline mutations in EDC4 may confer increased risk of breast cancer. Taking together our results suggest that EDC4 is a functional phenocopy of BRCA1 that could be targeted in cancer therapeutics
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