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cGAS suppresses genomic instability as a decelerator of replication forks

Hao Chen1,2, Hao Chen3, Jiamin Zhang1

  • 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA.

Science Advances
|October 15, 2020
PubMed

Insights

Cyclic GMP-AMP synthase (cGAS) normally slows DNA replication forks to prevent genomic instability. Loss of cGAS accelerates replication, increasing cancer cell sensitivity to DNA-damaging treatments.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Cyclic GMP-AMP synthase (cGAS) is a key sensor of cytosolic DNA, crucial for innate immunity.
  • cGAS is primarily cytoplasmic, but a fraction associates with chromatin.

Purpose of the Study:

  • To investigate the role of cGAS in DNA replication dynamics and genomic stability.
  • To determine if cGAS directly impacts replication forks independently of its signaling pathway.

Main Methods:

  • Cellular assays to assess DNA replication, proliferation, and genomic instability in cGAS-deficient cells.
  • Analysis of cGAS interaction with replication fork proteins and chromatin association.
  • Functional studies on replication fork speed and stability.

Main Results:

  • Loss of cGAS leads to uncontrolled DNA replication, hyperproliferation, and genomic instability.
  • cGAS binds to DNA in the nucleus and directly slows replication forks, independent of cGAMP/STING.
  • cGAS-deficient cells exhibit accelerated but unstable replication forks, leading to replication stress.

Conclusions:

  • cGAS acts as a nuclear decelerator of DNA replication forks, maintaining replication dynamics and suppressing DNA damage.
  • cGAS deficiency sensitizes cells to replication stress, radiation, and chemotherapy.
  • cGAS is a potential therapeutic target for exploiting cancer cell genomic instability.

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