title: Wwox-Brca1 interaction: role in DNA repair pathway choice.
abstract: 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.
authors.affiliation: Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Schrock
authors.affiliation: Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: B
authors.initials: B
authors.lastname: Batar
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: T
authors.initials: T
authors.lastname: Druck
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Ferguson
authors.affiliation: Department of Radiation Oncology and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Cho
authors.affiliation: Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: K
authors.initials: K
authors.lastname: Akakpo
authors.affiliation: Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: H
authors.initials: H
authors.lastname: Hagrass
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Heerema
authors.affiliation: Department of Radiation Oncology and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: F
authors.initials: F
authors.lastname: Xia
authors.affiliation: Division of Computational Biology and Bioinformatics, Department of Biomedical Informatics and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Parvin
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Aldaz
authors.affiliation: Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: K
authors.initials: K
authors.lastname: Huebner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019313:BRCA1 Protein / Q000378:metabolism*; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology; D059766:DNA End-Joining Repair; D004351:Drug Resistance; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D010088:Oxidoreductases / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains; D011839:Radiation, Ionizing; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; C428130:Wwox protein, mouse; C586509:Brap protein, mouse; D044767:Ubiquitin-Protein Ligases; D002945:Cisplatin