The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability

• Published in: Cell research Vol. 23; no. 12; pp. 1396 - 1413
• Main Authors: Min, Jin-Na, Tian, Yanyan, Xiao, Yang, Wu, Ling, Li, Lei, Chang, Sandy
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2013; Nature Publishing Group
• Subjects: 631/208/211; 631/337/100/102; 631/80/103/560; 631/80/641/151; Alleles; Animals; Biomedical and Life Sciences; Cell Biology; Cells, Cultured; Cellular Senescence; Chromatin - metabolism; Chromatin Assembly and Disassembly; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded; DNA Helicases - deficiency; DNA Helicases - genetics; DNA Helicases - metabolism; DNA Repair; DNA Replication - drug effects; Embryonic growth stage; Embryos; Fibroblasts - cytology; Fibroblasts - metabolism; Genomic Instability; Hydroxyurea - pharmacology; Life Sciences; Mammals; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Nucleic Acid Synthesis Inhibitors - pharmacology; Original; original-article; Telomere - metabolism; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Yeasts; replication; cancer; genome instability; chromatin; DNA damage; telomere
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2013.113

The INO80 (inositol requiring mutant 80) chromatin remodeling complex plays important roles in transcriptional regulation and DNA replication and repair, and consists of several functional protein subunits, including the critical Ino80 ATPase catalytic subunit. While the function of INO80 has been studied in yeast and mammalian cell lines, we do not know how mIno80 contributes to the maintenance of genome stability to prevent cancer development in mice. Here, we use a conditional knockout approach to explore the cellular and organismal functions of mIno80. Deletion of mIno80 results in profound cellular proliferative defects and activation of p21-dependent cellular senescence. While mIno80 is required for efficient repair of DNA double strand breaks, its depletion did not impact upon the formation of γ-H2AX and 53BP1 DNA damage foci, or the activation of the ATM-CHK2-dependent DNA damage response. mIno80 deletion inhibited the generation of single-strand DNA, resulting in defects in homology-directed DNA repair (HDR) at telomeres. Fragile telomeres were prominent in mIno80 Δ/Δ MEFs, suggesting that chromatin remodeling is required for efficient telomere replication. mIno80 −/− mouse embryos die early during embryogenesis, while conditional deletion of mIno80 in adult mice results in weight loss and premature death. In a p53 −/− tumor-prone background, mIno80 haploinsufficiency favored the development of sarcomas. Our studies suggest that the mIno80 chromatin remodeling complex plays important roles in telomere replication, HDR-mediated repair of dysfunctional telomeres, and maintenance of genome stability.