Nuclear cGAS suppresses DNA repair and promotes tumorigenesis

Haipeng Liu, Haiping Zhang, Xiangyang Wu, Dapeng Ma, Juehui Wu, Lin Wang, Yan Jiang, Yiyan Fei, Chenggang Zhu, Rong Tan, Peter Jungblut, Gang Pei, Anca Dorhoi, Qiaoling Yan, Fan Zhang, Ruijuan Zheng, Siyu Liu, Haijiao Liang, Zhonghua Liu, Hua Yang, Jianxia Chen, Peng Wang, Tianqi Tang, Wenxia Peng, Zhangsen Hu, Zhu Xu, Xiaochen Huang, Jie Wang, Haohao Li, Yilong Zhou, Feng Liu, Dapeng Yan, Stefan H. E. Kaufmann, Chang Chen, Zhiyong Mao () and Baoxue Ge ()
Additional contact information
Haipeng Liu: Tongji University School of Medicine
Haiping Zhang: Tongji University
Xiangyang Wu: Tongji University School of Medicine
Dapeng Ma: Tongji University School of Medicine
Juehui Wu: Tongji University School of Medicine
Lin Wang: Tongji University School of Medicine
Yan Jiang: Tongji University School of Medicine
Yiyan Fei: Fudan University
Chenggang Zhu: Fudan University
Rong Tan: Central South University
Peter Jungblut: Max Planck Institute for Infection Biology
Gang Pei: Department of Immunology, Max Planck Institute for Infection Biology
Anca Dorhoi: Department of Immunology, Max Planck Institute for Infection Biology
Qiaoling Yan: Tongji University School of Medicine
Fan Zhang: Tongji University School of Medicine
Ruijuan Zheng: Tongji University School of Medicine
Siyu Liu: Tongji University School of Medicine
Haijiao Liang: Tongji University School of Medicine
Zhonghua Liu: Tongji University School of Medicine
Hua Yang: Tongji University School of Medicine
Jianxia Chen: Tongji University School of Medicine
Peng Wang: Tongji University School of Medicine
Tianqi Tang: Tongji University School of Medicine
Wenxia Peng: Tongji University School of Medicine
Zhangsen Hu: Tongji University
Zhu Xu: Tongji University
Xiaochen Huang: Tongji University School of Medicine
Jie Wang: Tongji University School of Medicine
Haohao Li: Tongji University School of Medicine
Yilong Zhou: Tongji University School of Medicine
Feng Liu: Tongji University School of Medicine
Dapeng Yan: Fudan University
Stefan H. E. Kaufmann: Department of Immunology, Max Planck Institute for Infection Biology
Chang Chen: Tongji University School of Medicine
Zhiyong Mao: Tongji University
Baoxue Ge: Tongji University School of Medicine

Nature, 2018, vol. 563, issue 7729, 131-136

Abstract: 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.

Keywords: Double-strand Breaks; Nonhomologous End Joining (NHEJ); Tongji University School; Human Skin Fibroblast Cell; γH2AX-positive Cells (search for similar items in EconPapers)
Date: 2018
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Citations: View citations in EconPapers (4)

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DOI: 10.1038/s41586-018-0629-6

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