Wednesday, December 24, 2025 12/24/2025

DNA ligase activities during base excision repair coordination

Award Number: R35GM147111
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2022
PERIOD OF PERFORMANCE END DATE: 10/31/2025

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DNA ligase activities during base excision repair coordination - PROJECT SUMMARY Base excision repair (BER) is a critical mechanism for preventing the mutagenic and lethal consequences of DNA damage generated by endogenous reactive chemical species or exposure to environmental hazards. BER is multi-step pathway that requires a tight coordination between the repair proteins. The downstream steps of BER pathway involves gap filling by DNA polymerase (pol) β and subsequent nick sealing by DNA ligase (ligase I or IIIα). This step-to-step coordination is orchestrated by non-enzymatic scaffolding protein X-Ray Repair Cross Complementing 1 (XRCC1) that plays a key role in assembling repair proteins. Although the roles of the individual enzymes are largely studied, how the multi-protein BER complex coordinates while maintaining the repair efficiency remains unclear. Though often considered an accurate process, the BER can contribute to genome instability if normal coordination breaks down. For example, the mutations in the polβ gene that have been found in many human cancers result in the modifications in its repair functions that impair BER efficiency. Similarly, XRCC1 cancer-associated variants with a defective scaffolding role predispose the cell to genomic instability and transformation. Failure in the BER pathway coordination could result in the formation of strand-break repair intermediates that are more mutagenic or toxic than the initial DNA lesions. My research program will fill the important gap of knowledge in the BER field by elucidating the molecular components of multi-protein BER complex that are necessary for accurate repair and define the ramifications of defective pathway coordination during DNA ligase I and IIIα activities. We are in a unique position to advance this scientific front based on our strong track record and our multidisciplinary approach. In Project 1, we build off our substantial prior work using biochemical and biophysical approach to define the molecular mechanism by which polβ, DNA ligases I and IIIα execute the repair pathway coordination. Our studies will also elucidate cancer-associated XRCC1 and polβ variants with altered BER functions as an important determinants of defective pathway coordination. In Project 2, using X-ray crystallography, we will elucidate the features of DNA substrate and ligase interaction that dictate accurate versus mutagenic outcomes during final nick sealing step at atomic resolution. This project will be extended with cryo-EM to define the structural architecture of large BER multi-protein complexes scaffolded by XRCC1 that dictates accurate repair pathway coordination. With these 2 Projects, my laboratory will launch a new and unique aspect of the research conducted by my group which seeks to better understand the mechanism by which a multi-protein repair complex coordinate during BER and answer several key questions regarding how a tight coordination is vital for maintaining the integrity of our genomic DNA, functions normally and how altering these functions stemming from a failure in the repair pathway coordination leads to disease.


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: 2026 ( Subtotal = $6,609 )
2026	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	4	12/19/2025	NON-COMPETING CONTINUATION	-$147,473
2026	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Biomedical Research and Research Training	001	5	12/19/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$154,082
														Subtotal = $6,609

Issue Date FY: 2025 ( Subtotal = $374,065 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	4	5/14/2025	NON-COMPETING CONTINUATION	$374,065
														Subtotal = $374,065

Issue Date FY: 2024 ( Subtotal = $374,065 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	3	5/9/2024	NON-COMPETING CONTINUATION	$374,065
														Subtotal = $374,065

Issue Date FY: 2023 ( Subtotal = $574,065 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	001	2	9/8/2023	SUPPLEMENT FOR EXPANSION	$200,000
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	2	5/29/2023	NON-COMPETING CONTINUATION	$374,065
														Subtotal = $574,065

Issue Date FY: 2022 ( Subtotal = $374,065 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	1	8/8/2022	NEW	$374,065
														Subtotal = $374,065

Grand Total All Awards = $1,702,869

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DNA ligase activities during base excision repair coordination

Award Number: R35GM147111

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2022

PERIOD OF PERFORMANCE END DATE: 10/31/2025

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