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ATF3 Regulation of Histone Acetylation in Genome Maintenance

Award Number: R01CA240966
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/10/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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ATF3 Regulation of Histone Acetylation in Genome Maintenance - Project Summary A better understanding of the DNA damage response (DDR) is of utmost importance because this evolutionally-conserved genome-maintaining mechanism not only serves as an anti-cancer barrier, but influences efficacies of radiation therapy and chemotherapy that mainly kill cancer cells by inducing DNA damage. Whereas DNA is embedded in highly-ordered chromatin, DNA damage promptly induces chromatin alterations at sites of damage. One such early change, histone acetylation catalyzed by histone acetyltransferases Tip60 and p300/CBP, not only can promote chromatin access to the DNA-repair machinery, but can regulate DNA-repair pathway choice. As histone acetylation has emerged as a principal mechanism for coordinating DDR, it is of significance to identify genes that can regulate this event upon DNA damage. Activating transcription factor 3 (ATF3) is a stress sensor commonly induced by DNA-damaging agents. We have demonstrated that ATF3 can activate the tumor suppressor p53 while promoting Tip60-mediated activation of the major DDR kinase ATM. We also found that ATF3 is required for genome maintenance and the suppression of spontaneous tumorigenesis in mice. Whereas these results support that ATF3 plays an indispensable role in the DNA damage response, what is currently unknown is whether ATF3 can also actively regulate chromatin dynamics and DNA repair independent of its regulation on p53 and Tip60. The objective of this application is to address this question, and to determine the role of ATF3 in the regulation of DNA repair at the chromatin level. Formulated on the basis of compelling preliminary data, the central hypothesis is that ATF3 recruited to sites of DNA damage promotes p300/CBP to acetylate H3 facilitating the loading of repair proteins for non-homologous end-joining (NHEJ). To test this hypothesis, we will determine how ATF3 is recruited to DSBs and promotes p300/CBP-catalyzed histone acetylation at DSBs (Aim 1). We will also delineate how histone acetylation regulated by ATF3 alters chromatin structure and facilitates the recruitments of NHEJ factors (Aim 2). Lastly, we will also use the IR-induced lymphomagenesis mouse model to assess the functional significance of our novel findings (Aim 3). Completion of the proposed research is expected to define a novel role that ATF3 plays in genome maintenance, and discover novel mechanisms by which the early chromatin response to DNA damage is regulated.


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 = $352,275 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Cause and Prevention Research	000	5	3/3/2025	NON-COMPETING CONTINUATION	$317,048
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Cause and Prevention Research	001	5	6/16/2025	NON-COMPETING CONTINUATION	$35,227
														Subtotal = $352,275

Issue Date FY: 2024 ( Subtotal = $334,662 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Cause and Prevention Research	000	4	3/20/2024	NON-COMPETING CONTINUATION	$317,048
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Cause and Prevention Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$17,614
														Subtotal = $334,662

Issue Date FY: 2023 ( Subtotal = $345,230 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Cause and Prevention Research	000	3	3/6/2023	NON-COMPETING CONTINUATION	$345,230
														Subtotal = $345,230

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Cause and Prevention Research	000	2	7/11/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $352,275 )
2021	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Cause and Prevention Research	000	2	3/18/2021	NON-COMPETING CONTINUATION	$352,275
														Subtotal = $352,275

Issue Date FY: 2020 ( Subtotal = $351,418 )
2020	2020	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Cause and Prevention Research	000	1	4/10/2020	NEW	$351,418
														Subtotal = $351,418

Grand Total All Awards = $1,735,860

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ATF3 Regulation of Histone Acetylation in Genome Maintenance

Award Number: R01CA240966

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/10/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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