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Structural and Mechanistic Studies of DNA Repair

Award Number: R35GM128562
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: 09/01/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Structural and Mechanistic Studies of DNA Repair - Oxidative stress is a prevalent and dangerous cellular condition resulting in deleterious modifications to the structure of DNA. These modifications promote mutagenesis and consequently the development of numerous human maladies, including cancer. The base excision repair (BER) pathway is the cells primary defense against oxidative DNA damage and is a vital guardian of genome stability. While the roles of individual enzymes during a classical BER cycle are largely established, it remains enigmatic how these enzymes function together in a multi-protein/DNA complex to facilitate the channeling of toxic DNA repair intermediates between each protein. Importantly, BER not only occurs on naked duplex DNA, but also within chromatin that is composed of nucleosomes. These nucleosomes present a barrier to BER enzymes accessing and effectively repairing DNA damage. The mechanisms by which DNA repair proteins overcome this barrier to repair DNA damage in the nucleosome is poorly understood. The major goals of this proposal are to understand the molecular mechanisms of each BER factor both individually and within larger multi-protein/DNA complexes using naked duplex DNA and chromatin; and to decipher the molecular mechanism by which telomerase replicates the telomere. Elegant biophysical approaches are required to elucidate these BER complexities and to provide both a foundation for interpreting the biological response and the development of therapeutic treatments. We are in a unique position to advance this scientific front based on my strong track record in DNA damage and repair, assembled team of collaborators, and multidisciplinary approach. To meet this goal, we utilize a comprehensive approach of time- lapse X-ray crystallography, molecular dynamic simulations, enzyme kinetics, single-molecule total internal reflection microscopy, and cryo-EM. Using these methodologies, we will determine 1) how do new fundamental mechanistic steps alter the DNA polymerase and telomerase mechanism; 2) how do individual BER enzymes assemble into a multi-protein/DNA complex to facilitate the channeling of toxic DNA intermediates; 3) how are multi-protein/DNA BER complexes structurally organized; 4) how is DNA damage identified and repaired within nucleosomes; and 5) how are multi-protein/DNA BER complexes formed on nucleosomes containing DNA damage. This set of questions will go from an atomic level mechanistic understanding of key BER components to the structural and dynamic interactions within the entire BER multi-protein complex. By doing this, we will lay the foundation to address an inherent challenge in establishing cellular models and developing new therapeutic treatments that target DNA repair. With this information in hand, we will be closer to our long-term goal of providing a basis for rational drug design towards the development of more effective chemotherapeutics and synergistic drug combinations that target proteins involved in the DNA damage response.


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 = $465,000 )
2025	2025	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Biomedical Research and Research Training	001	8	8/13/2025	NON-COMPETING CONTINUATION	$465,000
2025	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Biomedical Research and Research Training	000	7	11/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $465,000

Issue Date FY: 2024 ( Subtotal = $655,000 )
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Biomedical Research and Research Training	001	7	8/23/2024	NON-COMPETING CONTINUATION	$465,000
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Biomedical Research and Research Training	002	7	9/6/2024	SUPPLEMENT FOR EXPANSION	$190,000
2024	2022	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Biomedical Research and Research Training	000	5	7/31/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $655,000

Issue Date FY: 2023 ( Subtotal = $465,000 )
2023	2023	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Biomedical Research and Research Training	000	6	9/4/2023	COMPETING CONTINUATION	$465,000
														Subtotal = $465,000

Issue Date FY: 2022 ( Subtotal = $354,385 )
2022	2022	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Biomedical Research and Research Training	001	5	8/31/2022	NON-COMPETING CONTINUATION	$382,500
2022	2021	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Biomedical Research and Research Training	000	4	4/28/2022	SUPPLEMENT FOR EXPANSION	-$28,115
														Subtotal = $354,385

Issue Date FY: 2021 ( Subtotal = $410,615 )
2021	2021	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Biomedical Research and Research Training	000	4	9/1/2021	NON-COMPETING CONTINUATION	$382,500
2021	2021	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Biomedical Research and Research Training	001	4	9/3/2021	SUPPLEMENT FOR EXPANSION	$28,115
														Subtotal = $410,615

Issue Date FY: 2020 ( Subtotal = $579,310 )
2020	2020	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Biomedical Research and Research Training	000	2	11/20/2019	SUPPLEMENT FOR EXPANSION	$84,347
2020	2020	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Biomedical Research and Research Training	001	3	8/26/2020	NON-COMPETING CONTINUATION	$494,963
														Subtotal = $579,310

Issue Date FY: 2019 ( Subtotal = $382,500 )
2019	2019	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Biomedical Research and Research Training	000	2	8/14/2019	NON-COMPETING CONTINUATION	$382,500
														Subtotal = $382,500

Issue Date FY: 2018 ( Subtotal = $382,500 )
2018	2018	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Biomedical Research and Research Training	000	1	8/10/2018	NEW	$382,500
														Subtotal = $382,500

Grand Total All Awards = $3,694,310

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Structural and Mechanistic Studies of DNA Repair

Award Number: R35GM128562

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: 09/01/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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