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; Baoxue Ge

doi:10.1038/s41586-018-0629-6

Nuclear cGAS suppresses DNA repair and promotes tumorigenesis

Nature. 2018 Nov;563(7729):131-136. doi: 10.1038/s41586-018-0629-6. Epub 2018 Oct 24.

Authors

Haipeng Liu^#^{1

2}, Haiping Zhang^#³, Xiangyang Wu^#^{1

2}, Dapeng Ma², Juehui Wu^{1

2}, Lin Wang^{1

2}, Yan Jiang², Yiyan Fei⁴, Chenggang Zhu⁴, Rong Tan⁵, Peter Jungblut⁶, Gang Pei⁷, Anca Dorhoi^{7

8}, Qiaoling Yan², Fan Zhang⁹, Ruijuan Zheng¹, Siyu Liu², Haijiao Liang^{1

2}, Zhonghua Liu¹, Hua Yang¹, Jianxia Chen^{1

2}, Peng Wang², Tianqi Tang², Wenxia Peng², Zhangsen Hu³, Zhu Xu³, Xiaochen Huang¹, Jie Wang¹, Haohao Li¹, Yilong Zhou^{1

2}, Feng Liu¹, Dapeng Yan¹⁰, Stefan H E Kaufmann⁷, Chang Chen⁹, Zhiyong Mao¹¹, Baoxue Ge^{12

13}

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 cascade^1,2. Recognition of ruptured micronuclei by cGAS links genome instability to the innate immune response^3,4, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Active Transport, Cell Nucleus
Adult
Animals
Cell Cycle Proteins / antagonists & inhibitors
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Nucleus / enzymology
Cell Nucleus / metabolism*
Cell Transformation, Neoplastic / pathology*
DNA Breaks, Double-Stranded
DNA Damage
Female
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
Intracellular Signaling Peptides and Proteins / metabolism
Male
Membrane Proteins / metabolism
Mice
Mice, Inbred C57BL
Neoplasm Proteins / metabolism
Neoplasms / genetics
Neoplasms / metabolism*
Neoplasms / pathology*
Nucleotidyltransferases / deficiency
Nucleotidyltransferases / metabolism*
Phosphorylation
Phthalazines / pharmacology
Piperazines / pharmacology
Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
Poly (ADP-Ribose) Polymerase-1 / metabolism
Protein Binding / drug effects
Recombinational DNA Repair* / genetics
src-Family Kinases / metabolism

Substances

Cell Cycle Proteins
Intracellular Signaling Peptides and Proteins
JTB protein, human
Membrane Proteins
Neoplasm Proteins
Phthalazines
Piperazines
TIMELESS protein, human
PARP1 protein, human
Poly (ADP-Ribose) Polymerase-1
BLK protein, human
src-Family Kinases
Nucleotidyltransferases
cGAS protein, human
cGAS protein, mouse
olaparib