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Mechanistic characterization of replisome components during replication stress

Award Number: R35GM137800
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: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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Mechanistic characterization of replisome components during replication stress - PROJECT SUMMARY Tens of thousands of replication forks duplicate both genetic and epigenetic information faithfully in each S-phase of cell cycle. Progression of replisomes, the macromolecular complexes that execute DNA synthesis, is often hindered by DNA lesions resulting in fork stalling events. Such perturbations activate the replication stress response that stabilize stalled forks to prevent irreversible collapse into double strand breaks. Replication stress response engages several proteins to remodel replication forks, activate DNA repair pathways and amplify replication checkpoint. Defective replication stress response engenders conditions associated with developmental abnormalities, accelerated aging, and tumorigenesis. Moreover, oncogene- induced replication stress is a key driver of chromosomal instability and cellular transformation. Thus, it is critical to elucidate the genome maintenance pathways that resolve replication stress to safeguard genome integrity. The primary goal of our research program is to understand genome maintenance pathways that promote accurate replication of the genome. Achieving this objective requires screening the composition of replication fork proteomes and mechanistic characterization of replisome proteins to elucidate their function in replication stress response. To this end, my lab has uncovered fork protection factors that block digestion of newly synthesized DNA by resection nucleases. Furthermore, we established that chromatin state is a critical determinant in replication fork protection and identified repair pathways that alter fork stability in BRCA-deficient cancers. We also characterized the contribution of nucleosome remodeling at replication forks, and identified proper chromatin assembly on daughter DNA molecules is necessary to prevent gap accumulation and break induction. These innovative contributions make us ideally poised to pursue detailed functional studies to uncover replication stress response pathways that function in promoting genome integrity. The research proposal will address three key goals – 1. Characterization of fork protection pathways, 2. Regulation of nascent ssDNA gap formation, and 3. Investigation of replication stress response during re-replication. Successful completion of these goals will provide critical insights into the fundamental mechanisms utilized by cells to deal with replication stress to promote genome stability. By exploring the scientific objectives using hypothesis-driven research, the proposed research will lead to significant breakthroughs and paradigm-shifting discoveries thereby enhancing our knowledge on mechanisms that control DNA replication and providing opportunities to target replication fork vulnerabilities for cancer treatment.


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 = $424,361 )
2026	2026	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Biomedical Research and Research Training	001	6	2/20/2026	COMPETING CONTINUATION	$424,361
2026	2024	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	5	2/16/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $424,361

Issue Date FY: 2024 ( Subtotal = $364,140 )
2024	2024	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	5	5/9/2024	NON-COMPETING CONTINUATION	$364,140
														Subtotal = $364,140

Issue Date FY: 2023 ( Subtotal = $364,140 )
2023	2023	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	4	5/11/2023	NON-COMPETING CONTINUATION	$364,140
														Subtotal = $364,140

Issue Date FY: 2022 ( Subtotal = $364,140 )
2022	2022	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	3	5/6/2022	NON-COMPETING CONTINUATION	$364,140
														Subtotal = $364,140

Issue Date FY: 2021 ( Subtotal = $410,550 )
2021	2021	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Biomedical Research and Research Training	001	2	8/2/2021	SUPPLEMENT FOR EXPANSION	$46,410
2021	2021	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	2	5/26/2021	NON-COMPETING CONTINUATION	$364,140
														Subtotal = $410,550

Issue Date FY: 2020 ( Subtotal = $347,014 )
2020	2020	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	1	6/26/2020	NEW	$347,014
														Subtotal = $347,014

Grand Total All Awards = $2,274,345

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Mechanistic characterization of replisome components during replication stress

Award Number: R35GM137800

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: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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