Journal
NATURE
Volume 563, Issue 7729, Pages 131-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-018-0629-6
Keywords
-
Categories
Funding
- Chinese National Program on Key Basic Research Project [2017YFA0505900, 2015CB964800]
- National Natural Science Foundation of China [81770006, 81370108, 91542111, 31030028, 81622019, 31570813]
- Shanghai Pujiang Program [16PJ1408600]
- Shanghai Medical and Health Services Outstanding Youth Talent Program [2017YQ078]
Ask authors/readers for more resources
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-alpha, 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available