Overexpression of the scaffold WD40 protein WRAP53β enhances the repair of and cell survival from DNA double-strand breaks
| Autor: | Thomas Helleday, Stefanie Böhm, Helge Gad, Elisabeth Hedström, Marianne Farnebo, Hanif Rassoolzadeh, Sofia Henriksson |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research DNA End-Joining Repair DNA repair Ubiquitin-Protein Ligases Immunology Coiled Bodies Histones 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Cell Line Tumor Humans Protein Isoforms DNA Breaks Double-Stranded RNA Small Interfering Telomerase Osteoblasts biology Ubiquitination Nuclear Proteins Recombinational DNA Repair Cell Biology DNA DNA repair protein XRCC4 Telomere Chromatin Proliferating cell nuclear antigen Ubiquitin ligase DNA-Binding Proteins Gene Expression Regulation Neoplastic 030104 developmental biology Cajal body 030220 oncology & carcinogenesis biology.protein Cancer research Original Article Homologous recombination Molecular Chaperones Signal Transduction |
| Zdroj: | Cell Death & Disease |
| Popis: | Altered expression of the multifunctional protein WRAP53β (WD40 encoding RNA Antisense to p53), which targets repair factors to DNA double-strand breaks and factors involved in telomere elongation to Cajal bodies, is linked to carcinogenesis. While loss of WRAP53β function has been shown to disrupt processes regulated by this protein, the consequences of its overexpression remain unclear. Here we demonstrate that overexpression of WRAP53β disrupts the formation of and impairs the localization of coilin to Cajal bodies. At the same time, the function of this protein in the repair of DNA double-strand breaks is enhanced. Following irradiation, cells overexpressing WRAP53β exhibit more rapid clearance of phospho-histone H2AX (γH2AX), and more efficient homologous recombination and non-homologous end-joining, in association with fewer DNA breaks. Moreover, in these cells the ubiquitylation of damaged chromatin, which is known to facilitate the recruitment of repair factors and subsequent repair, is elevated. Knockdown of the ubiquitin ligase involved, ring-finger protein 8 (RNF8), which is recruited to DNA breaks by WRAP53β, attenuated this effect, suggesting that overexpression of WRAP53β leads to more rapid repair, as well as improved cell survival, by enhancing RNF8-mediated ubiquitylation at DNA breaks. Our present findings indicate that WRAP53β and RNF8 are rate-limiting factors in the repair of DNA double-strand breaks and raise the possibility that upregulation of WRAP53β may contribute to genomic stability in and survival of cancer cells. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|