Li Shibo, Lu Hongyan, Wang Zi, Hu Qing, Wang Hongjun, Xiang Rong, Chiba Takuya, Wu Xiaohua
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA; School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China.
iScience. 2019 Jun 28;16:63-78. doi: 10.1016/j.isci.2019.05.017. Epub 2019 May 16.
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.
结构特异性核酸内切酶ERCC1/XPF在核苷酸切除修复和链间交联修复中发挥重要作用。在本研究中，我们确定了ERCC1/XPF在DNA双链断裂（DSB）修复中的新功能。我们发现，ERCC1/XPF在DSB处去除非同源序列的保守功能是哺乳动物细胞中同源重组的限速步骤，更重要的是，我们揭示了ERCC1/XPF在含有DNA二级结构的DSB修复中不可或缺的作用，这些二级结构包括源自常见脆性位点的富含AT的易形成结构的DNA序列和G-四链体（G4s）。我们还证明了XPF与参与去除DNA二级结构的DNA转位酶FANCM之间存在合成致死相互作用。此外，XPF失活使FANCM缺陷细胞对G4相互作用化合物敏感。这些结果表明ERCC1/XPF在保护DNA二级结构方面具有重要功能，并为通过抑制XPF对FANCM缺陷肿瘤进行靶向治疗提供了理论依据。
