Faculty Collaboration Database

Wwox-Brca1 interaction: role in DNA repair pathway choice. Oncogene 2017 Apr 20;36(16):2215-2227

Date

11/22/2016

Pubmed ID

27869163

Pubmed Central ID

PMC5398941

DOI

10.1038/onc.2016.389

Scopus ID

2-s2.0-84996835639 (requires institutional sign-in at Scopus site)   39 Citations

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.

Author List

Schrock MS, Batar B, Lee J, Druck T, Ferguson B, Cho JH, Akakpo K, Hagrass H, Heerema NA, Xia F, Parvin JD, Aldaz CM, Huebner K

Author

Kenneth Akakpo MD Assistant Professor in the Otolaryngology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antineoplastic Agents
BRCA1 Protein
Brain Neoplasms
Cell Line
Cell Survival
Cisplatin
DNA End-Joining Repair
Drug Resistance
Female
HeLa Cells
Humans
Mice
Mice, Knockout
Mice, Nude
Oxidoreductases
Protein Binding
Protein Domains
Radiation, Ionizing
Tumor Suppressor Proteins
Ubiquitin-Protein Ligases
WW Domain-Containing Oxidoreductase