TY - JOUR
T1 - Molecular biology cGAS suppresses genomic instability as a decelerator of replication forks
AU - Chen, Hao
AU - Chen, Hao
AU - Zhang, Jiamin
AU - Wang, Yumin
AU - Simoneau, Antoine
AU - Yang, Hui
AU - Levine, Arthur S.
AU - Zou, Lee
AU - Chen, Zhijian
AU - Lan, Li
N1 - Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved;
PY - 2020/10
Y1 - 2020/10
N2 - The cyclic GMP-AMP synthase (cGAS), a sensor of cytosolic DNA, is critical for the innate immune response. Here, we show that loss of cGAS in untransformed and cancer cells results in uncontrolled DNA replication, hyper-proliferation, and genomic instability. While the majority of cGAS is cytoplasmic, a fraction of cGAS associates with chromatin. cGAS interacts with replication fork proteins in a DNA binding–dependent manner, suggesting that cGAS encounters replication forks in DNA. Independent of cGAMP and STING, cGAS slows replication forks by binding to DNA in the nucleus. In the absence of cGAS, replication forks are accelerated, but fork stability is compromised. Consequently, cGAS-deficient cells are exposed to replication stress and become increasingly sensitive to radiation and chemotherapy. Thus, by acting as a decelerator of DNA replication forks, cGAS controls replication dynamics and suppresses replication-associated DNA damage, suggesting that cGAS is an attractive target for exploiting the genomic instability of cancer cells.
AB - The cyclic GMP-AMP synthase (cGAS), a sensor of cytosolic DNA, is critical for the innate immune response. Here, we show that loss of cGAS in untransformed and cancer cells results in uncontrolled DNA replication, hyper-proliferation, and genomic instability. While the majority of cGAS is cytoplasmic, a fraction of cGAS associates with chromatin. cGAS interacts with replication fork proteins in a DNA binding–dependent manner, suggesting that cGAS encounters replication forks in DNA. Independent of cGAMP and STING, cGAS slows replication forks by binding to DNA in the nucleus. In the absence of cGAS, replication forks are accelerated, but fork stability is compromised. Consequently, cGAS-deficient cells are exposed to replication stress and become increasingly sensitive to radiation and chemotherapy. Thus, by acting as a decelerator of DNA replication forks, cGAS controls replication dynamics and suppresses replication-associated DNA damage, suggesting that cGAS is an attractive target for exploiting the genomic instability of cancer cells.
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U2 - 10.1126/sciadv.abb8941
DO - 10.1126/sciadv.abb8941
M3 - Article
C2 - 33055160
AN - SCOPUS:85093488324
SN - 2375-2548
VL - 6
JO - Science Advances
JF - Science Advances
IS - 42
M1 - eabb8941
ER -