DNA复制因子CDT1
DNA复制
基因组不稳定性
染色体复制控制
DNA再复制
原点识别复合体
细胞生物学
生物
真核细胞DNA复制
复制因子C
染色质
DNA
遗传学
DNA损伤
作者
Hao Chen,Jiamin Zhang,Yumin Wang,Antoine Simoneau,Hui Yang,Arthur S. Levine,Lee Zou,Zhijian Chen,Li Lan
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2020-10-16
卷期号:6 (42)
被引量:75
标识
DOI:10.1126/sciadv.abb8941
摘要
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, hyperproliferation, 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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