ERCC1/XPF Is Important for Repair of DNA Double-Strand Breaks Containing Secondary Structures
Shibo Li,
Hongyan Lu,
Zi Wang,
Qing Hu,
Hongjun Wang,
Rong Xiang,
Takuya Chiba,
Xiaohua Wu
Affiliations
Shibo Li
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Hongyan Lu
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA; School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China
Zi Wang
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA; Biomedical Gerontology Laboratory, Department of Health Science and Social Welfare, School of Human Sciences, Waseda University, 2-579-15 Mikajima, Tokorozawa 359-1192, Japan
Qing Hu
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Hongjun Wang
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Rong Xiang
School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China
Takuya Chiba
Biomedical Gerontology Laboratory, Department of Health Science and Social Welfare, School of Human Sciences, Waseda University, 2-579-15 Mikajima, Tokorozawa 359-1192, Japan
Xiaohua Wu
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA; Corresponding author
Summary: The structure-specific endonuclease ERCC1/XPF plays an important role in nucleotide excision repair and interstrand cross-link repair. In this study, we identified new functions of ERCC1/XPF in DNA double-strand break (DSB) repair. We found that the conserved function of ERCC1/XPF to remove non-homologous sequences at DSBs is a rate-limiting step for homologous recombination in mammalian cells, and more importantly, we uncovered an indispensable role of ERCC1/XPF in repair of DSBs containing DNA secondary structures, including the structure-prone AT-rich DNA sequences derived from common fragile sites and G-quadruplexes (G4s). We also demonstrated a synthetic lethal interaction of XPF with DNA translocase FANCM that is involved in removing DNA secondary structures. Furthermore, inactivation of XPF sensitizes FANCM-deficient cells to G4-interacting compounds. These results suggest an important function of ERCC1/XPF in protecting DNA secondary structures and provide a rationale for targeted treatment of FANCM-deficient tumors through inhibition of XPF. : Biological Sciences; Molecular Biology; Cell Biology Subject Areas: Biological Sciences, Molecular Biology, Cell Biology
