2. Academic Validation
  3. Nuclear cGAS suppresses DNA repair and promotes tumorigenesis

Nuclear cGAS suppresses DNA repair and promotes tumorigenesis

  • Nature. 2018 Nov;563(7729):131-136. doi: 10.1038/s41586-018-0629-6.
Haipeng Liu  # 1 2,  Haiping Zhang  # 3,  Xiangyang Wu  # 1 2,  Dapeng Ma 2,  Juehui Wu 1 2,  Lin Wang 1 2,  Yan Jiang 2,  Yiyan Fei 4,  Chenggang Zhu 4,  Rong Tan 5,  Peter Jungblut 6,  Gang Pei 7,  Anca Dorhoi 7 8,  Qiaoling Yan 2,  Fan Zhang 9,  Ruijuan Zheng 1,  Siyu Liu 2,  Haijiao Liang 1 2,  Zhonghua Liu 1,  Hua Yang 1,  Jianxia Chen 1 2,  Peng Wang 2,  Tianqi Tang 2,  Wenxia Peng 2,  Zhangsen Hu 3,  Zhu Xu 3,  Xiaochen Huang 1,  Jie Wang 1,  Haohao Li 1,  Yilong Zhou 1 2,  Feng Liu 1,  Dapeng Yan 10,  Stefan H E Kaufmann 7,  Chang Chen 9,  Zhiyong Mao 11,  Baoxue Ge 12 13
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
  • 2 Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
  • 3 Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
  • 4 Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Fudan University, Shanghai, China.
  • 5 Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.
  • 6 Protein Purification Core Facility, Max Planck Institute for Infection Biology, Berlin, Germany.
  • 7 Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
  • 8 Institute of Immunology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald Insel Riems, Germany.
  • 9 Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
  • 10 Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai, China.
  • 11 Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China. zhiyong_mao@tongji.edu.cn.
  • 12 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. baoxue_ge@tongji.edu.cn.
  • 13 Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. baoxue_ge@tongji.edu.cn.
  • # Contributed equally.
PMID: 30356214 DOI: 10.1038/s41586-018-0629-6
Abstract

Accurate repair of DNA double-stranded breaks by homologous recombination preserves genome integrity and inhibits tumorigenesis. Cyclic GMP-AMP Synthase (cGAS) is a cytosolic DNA sensor that activates innate immunity by initiating the STING-IRF3-type I IFN signalling cascade1,2. Recognition of ruptured micronuclei by cGAS links genome instability to the innate immune response3,4, but the potential involvement of cGAS in DNA repair remains unknown. Here we demonstrate that cGAS inhibits homologous recombination in mouse and human models. DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-α, and the phosphorylation of cGAS at tyrosine 215-mediated by B-lymphoid tyrosine kinase-facilitates the cytosolic retention of cGAS. In the nucleus, cGAS is recruited to double-stranded breaks and interacts with PARP1 via poly(ADP-ribose). The cGAS-PARP1 interaction impedes the formation of the PARP1-Timeless complex, and thereby suppresses homologous recombination. We show that knockdown of cGAS suppresses DNA damage and inhibits tumour growth both in vitro and in vivo. We conclude that nuclear cGAS suppresses homologous-recombination-mediated repair and promotes tumour growth, and that cGAS therefore represents a potential target for Cancer prevention and therapy.

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