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Assembly and Dynamics of Molecular Machines in Genome Maintenance

Award Number: R35GM131704
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: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Assembly and Dynamics of Molecular Machines in Genome Maintenance - ABSTRACT Efficient genome maintenance is a double-edged sword. Accurate repair of DNA lesions and damaged replication forks promotes genome stability, which is a key to avoiding cancer, aging and neurodegenerative diseases associated with DNA repeat expansion. The same mechanisms that maintain genome integrity in healthy cells, allow cancer cells to acquire a more aggressive character and develop resistance to radiation and chemotherapy. Untimely deployment and/or dysregulation of the DNA repair machines may further destabilize the genome or may result in the accumulation of geno- and cytotoxic repair intermediates. Significant gaps remain in our understanding of the molecular events that funnel the intermediates of otherwise accurate repair into “rogue”, genome-destabilizing mechanisms. This research program emphasizes the molecular and structural mechanisms by which the intermediates of DNA metabolism bound by Replication Protein A (RPA) are channeled into DNA repair, protection of DNA replication forks, homologous recombination, DNA damage tolerance and signaling. Our central hypothesis is that the activities of the RAD51 recombinase, the ssDNA-binding protein RPA, recombination mediators BRCA2 (in human) and Rad52 (in yeast), and DNA repair helicases are finely tuned by a variety of factors, which include posttranslational modifications, interacting partner proteins, specific DNA structures and DNA lesions. These factors affect the protein configurational dynamics and critical protein-protein interfaces. Understanding how the protein plasticity and kinetics of assembly of the macromolecular machines of DNA repair will show us new ways to selectively manipulate the activities of RAD51, RPA and multifunctional DNA helicases and polymerases in DNA replication and repair. We are leveraging and building the tools of single-molecule biochemistry, biophysics, structural and chemical biology. Our unique perspective on the formation, activities and regulation of the nucleoprotein complexes orchestrating genome maintenance is rooted in our ability to visualize microscopic configurational dynamics of and sort individual human DNA repair proteins with their native posttranslational modifications, and to probe and separate activities associated with different surface-tethered proteins and nucleoprotein complexes at the single- molecule level. Our goal is to provide an entirely new outlook on how the cell balances the assembly and activities of the molecular machines that can repair, but also destabilize, the genome, and to be able to alter this balance with new chemotherapeutics targeting cancer and neurodegenerative diseases.


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 = $478,940 )
2025	2025	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	005	7	4/15/2025	NON-COMPETING CONTINUATION	$478,940
2025	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	004	6	2/14/2025	COMPETING CONTINUATION	$51,723
2025	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	000	6	11/21/2024	COMPETING CONTINUATION	$0
2025	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	002	5	2/14/2025	SUPPLEMENT FOR EXPANSION	-$8,602
2025	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	001	5	2/14/2025	NON-COMPETING CONTINUATION	-$41,534
2025	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	003	5	2/14/2025	SUPPLEMENT FOR EXPANSION	-$1,587
														Subtotal = $478,940

Issue Date FY: 2024 ( Subtotal = $685,020 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	001	6	8/27/2024	SUPPLEMENT FOR EXPANSION	$206,080
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	000	6	3/28/2024	COMPETING CONTINUATION	$478,940
														Subtotal = $685,020

Issue Date FY: 2023 ( Subtotal = $478,559 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	000	5	3/10/2023	NON-COMPETING CONTINUATION	$384,287
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	001	5	5/16/2023	SUPPLEMENT FOR EXPANSION	$14,685
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	002	5	5/19/2023	SUPPLEMENT FOR EXPANSION	$79,587
														Subtotal = $478,559

Issue Date FY: 2022 ( Subtotal = $384,287 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	001	4	7/21/2022	NON-COMPETING CONTINUATION	$38,432
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	000	4	3/16/2022	NON-COMPETING CONTINUATION	$345,855
														Subtotal = $384,287

Issue Date FY: 2021 ( Subtotal = $553,757 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	000	3	3/19/2021	NON-COMPETING CONTINUATION	$381,257
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	001	3	9/7/2021	SUPPLEMENT FOR EXPANSION	$172,500
														Subtotal = $553,757

Issue Date FY: 2020 ( Subtotal = $381,257 )
2020	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	000	2	3/16/2020	NON-COMPETING CONTINUATION	$381,257
														Subtotal = $381,257

Issue Date FY: 2019 ( Subtotal = $380,053 )
2019	2019	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	000	1	3/26/2019	NEW	$380,053
														Subtotal = $380,053

Grand Total All Awards = $3,341,873

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Assembly and Dynamics of Molecular Machines in Genome Maintenance

Award Number: R35GM131704

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: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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