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Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1.

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.

SUBMITTER: Hernandez G

PROVIDER: S-EPMC5840268 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1.

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

Nature communications 20180306 1

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 pr ...[more]

PMID: 29511213

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Project description:Background:In kindreds carrying path_BRCA1/2 variants, some women in these families will develop cancer despite testing negative for the family's pathogenic variant. These families may have additional genetic variants, which not only may increase the susceptibility of the families' path_BRCA1/2, but also be capable of causing cancer in the absence of the path_BRCA1/2 variants. We aimed to identify novel genetic variants in prospectively detected breast cancer (BC) or gynecological cancer cases tested negative for their families' pathogenic BRCA1/2 variant (path_BRCA1 or path_BRCA2). Methods:Women with BC or gynecological cancer who had tested negative for path_BRCA1 or path_BRCA2 variants were included. Forty-four cancer susceptibility genes were screened for genetic variation through a targeted amplicon-based sequencing assay. Protein- and RNA splicing-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as the ones most likely affecting pre-mRNA splicing were experimentally analyzed in a minigene assay. Results:We identified 48 women who were tested negative for their family's path_BRCA1 (n?=?13) or path_BRCA2 (n?=?35) variants. Pathogenic variants in the ATM, BRCA2, MSH6 and MUTYH genes were found in 10% (5/48) of the cases, of whom 15% (2/13) were from path_BRCA1 and 9% (3/35) from path_BRCA2 families. Out of the 26 unique VUS, 3 (12%) were predicted to affect RNA splicing (APC c.721G?>?A, MAP3K1 c.764A?>?G and MSH2 c.815C?>?T). However, by using a minigene, assay we here show that APC c.721G?>?A does not cause a splicing defect, similarly to what has been recently reported for the MAP3K1 c.764A?>?G. The MSH2 c.815C?>?T was previously described as causing partial exon skipping and it was identified in this work together with the path_BRCA2 c.9382C?>?T (p.R3128X). Conclusion:All women in breast or breast/ovarian cancer kindreds would benefit from being offered genetic testing irrespective of which causative genetic variants have been demonstrated in their relatives.

Project description:In this study, loss of expression of the fragile site-encoded Wwox protein was found to contribute to radiation and cisplatin resistance of cells, responses that could be associated with cancer recurrence and poor outcome. WWOX gene deletions occur in a variety of human cancer types, and reduced Wwox protein expression can be detected early during cancer development. We found that Wwox loss is followed by mild chromosome instability in genomes of mouse embryo fibroblast cells from Wwox-knockout mice. Human and mouse cells deficient for Wwox also exhibit significantly enhanced survival of ionizing radiation and bleomycin treatment, agents that induce double-strand breaks (DSBs). Cancer cells that survive radiation recur more rapidly in a xenograft model of irradiated breast cancer cells; Wwox-deficient cells exhibited significantly shorter tumor latencies vs Wwox-expressing cells. This Wwox effect has important consequences in human disease: in a cohort of cancer patients treated with radiation, Wwox deficiency significantly correlated with shorter overall survival times. In examining mechanisms underlying Wwox-dependent survival differences, we found that Wwox-deficient cells exhibit enhanced homology directed repair (HDR) and decreased non-homologous end-joining (NHEJ) repair, suggesting that Wwox contributes to DNA DSB repair pathway choice. Upon silencing of Rad51, a protein critical for HDR, Wwox-deficient cells were resensitized to radiation. We also demonstrated interaction of Wwox with Brca1, a driver of HDR, and show via immunofluorescent detection of repair proteins at ionizing radiation-induced DNA damage foci that Wwox expression suppresses DSB repair at the end-resection step of HDR. We propose a genome caretaker function for WWOX, in which Brca1-Wwox interaction supports NHEJ as the dominant DSB repair pathway in Wwox-sufficient cells. Taken together, the experimental results suggest that reduced Wwox expression, a common occurrence in cancers, dysregulates DSB repair, enhancing efficiency of likely mutagenic repair, and enabling radiation and cisplatin treatment resistance.

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Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1.

Publications

Decapping protein EDC4 regulates DNA repair and phenocopies BRCA1.

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