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Non-canonical cGAS signaling in DNA damage response

Award Number: R01AI148741
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/05/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Non-canonical cGAS signaling in DNA damage response - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $471,678 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	6	12/4/2024	NON-COMPETING CONTINUATION	$471,678
														Subtotal = $471,678

Issue Date FY: 2024 ( Subtotal = $806,825 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	001	5	5/16/2024	NON-COMPETING CONTINUATION	$48,626
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	5	10/31/2023	NON-COMPETING CONTINUATION	$437,641
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	002	5	6/7/2024	SUPPLEMENT FOR EXPANSION	$320,558
														Subtotal = $806,825

Issue Date FY: 2023 ( Subtotal = $486,267 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	4	11/23/2022	NON-COMPETING CONTINUATION	$486,267
														Subtotal = $486,267

Issue Date FY: 2021 ( Subtotal = $833,541 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	2	11/24/2020	NON-COMPETING CONTINUATION	$498,616
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	005	2	8/26/2021	NON-COMPETING CONTINUATION	$0
2021	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	007	3	8/31/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$55,011
2021	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	004	3	8/16/2021	SUPPLEMENT FOR EXPANSION	$342,681
2021	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	003	3	7/21/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2021	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	002	3	7/6/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$305,397
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	006	2	8/31/2021	NON-COMPETING CONTINUATION	-$55,011
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	001	2	7/6/2021	NON-COMPETING CONTINUATION	-$313,153
														Subtotal = $833,541

Issue Date FY: 2020 ( Subtotal = $496,391 )
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	001	1	8/24/2020	NEW	$40,000
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	1	12/4/2019	NEW	$456,391
														Subtotal = $496,391

Grand Total All Awards = $3,094,702

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Non-canonical cGAS signaling in DNA damage response

Award Number: R01AI148741

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/05/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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