# Non-canonical cGAS signaling in DNA damage response

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $185,463

## Abstract

SUMMARY
The vertebrate innate immunity relies upon a complex set of cytosolic pattern recognition receptors (PRR) to
detect pathogen-derived, evolutionarily conserved molecules such as DNA. The sensing of cytosolic DNA by
cyclic-GMP-AMP synthase (cGAS) activates the enzymatic synthesis of cyclic guanosine monophosphate-
adenosine monophosphate (cGAMP), a cyclic dinucleotide (CDN) second messenger. cGAMP signals via its
high affinity receptor protein STING, which subsequently recruits TANK-binding kinase 1 (TBK1) and interferon
(IFN) regulatory factor 3 (IRF3) to stimulate the induction of type I IFNs. Although originally identified as a
cytosolic sensor of foreign DNA, cGAS is also recruited to and activated by fragments of chromatin from
damaged genomic DNA in the cytosol or micronuclei.
Multiple convergent studies have recently highlighted the significance of cGAS in the DNA damage–induced
inflammatory response and its implications for cellular senescence, tumorigenesis, and metastasis. Nothing,
however, is known about whether cGAS activation in these contexts directly contributes to the maintenance
of genome integrity. Recent studies in our laboratory have discovered that cGAS/cGAMP signaling triggers
DNA damage response (DDR), independently of its well-characterized type I interferon pathway. These
studies revealed that cGAMP-induced DDR activates cell cycle checkpoint responses that lead to G1 arrest
and subsequent suppression of homology directed repair (HDR) of double-strand DNA breaks (DSB) in
CRISPR/Cas9-edited mouse embryos and human and mouse cells. Interestingly, the cGAMP-induced DDR
was also demonstrable in invertebrate species (oysters and starlet sea anemone) lacking interferon-based
immune system, suggesting that the DNA damage surveillance mechanism of cGAMP predates its more well-
known IFN-mediated immune function.
The studies proposed here aim to advance these novel findings by elucidating the molecular mechanism of
cGAS/cGAMP-induced DDR induction via three thematically integrated, yet independent Aims: (1) Decipher
the critical signaling pathways involved in cGAMP-induced ATM activation; (2) Define the molecular
mechanism of cGAS-cGAMP-induced suppression of HDR; and (3) Elucidate whether cGAMP-induced DDR
potentiates the cGAS-initiated innate immunity. In summary, this work will illuminate novel aspects of the
molecular and biochemical basis of cGAMP-induced activation of the apical DDR signaling kinase ATM, and
increase understanding of the relationship between cGAMP-induced DDR signaling and the traditional immune
function of cGAS.

## Key facts

- **NIH application ID:** 10064992
- **Project number:** 5R01AI148741-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Nagaraj Kerur
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $185,463
- **Award type:** 5
- **Project period:** 2019-12-05 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10064992

## Citation

> US National Institutes of Health, RePORTER application 10064992, Non-canonical cGAS signaling in DNA damage response (5R01AI148741-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10064992. Licensed CC0.

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