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Replication-Coupled Repair: a mechanism for surviving UV irradiation

Award Number: R21ES034880
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Replication-Coupled Repair: a mechanism for surviving UV irradiation - Project Summary Near UV radiation (254nm light) induces DNA damage that blocks replication can result in genomic rearrangements when it resumes from the wrong place, mutagenesis when the incorrect base is incorporated opposite to the lesion, or cell death when the block to replication cannot be overcome. Inaccurate replication in the presence of environmental mutagens such as UV is responsible for the majority of mutagenesis and rearrangements observed in cancer cells. Thus, understanding how disrupted replication forks are restored is critical to developing therapeutics and strategies for preventing instabilities associated with these events. In humans, the role of BRCA2 and RECQ proteins in maintaining and processing replication forks that encounter DNA damage is well known. However, the mechanism by which replication is restored remains unclear. Different models have suggested that either repair, translesion synthesis, or recombination may operate to allow replication to resume. Yet, these pathways do not all share equally beneficial outcomes. Whereas DNA repair is error free, translesion synthesis and recombination are associated with elevated rates of mutations and genome rearrangements respectively. Thus critical to advancing the field, is a clear determination of the mechanism by which DNA replication resumes following disruption. This work will demonstrate that replication forks disrupted by UV-induced DNA damage are primarily processed through a general recovery mechanism that allows nucleotide excision repair enzymes to access to the blocking lesion and effect repair. Most in vitro studies suggest that the replisome is disrupted by DNA lesions in the leading strand template, but not lagging strand template. Further leading strand lesion on plasmid substrates are preferentially processed through nucleotide excision repair. Thus the first aim of this proposal will utilize CPD-seq, an established high-throughput sequencing approach, to map the repair of UV lesions over time on E. coli genome and demonstrate that leading strand lesions are preferentially repaired during replication. The second aim of the proposal characterizes the role that holC, encoding the χ subunit of the replisome, play in the replication-coupled repair. holC mutations are epistatic with recF mutants which is specifically required to process and resume replication after disruption by UV-induced damage. Further, HolC (χ) is reported to physically interact with UvrA. Therefore this aim seeks to and demonstrate that the interaction occurs in response to and functions following UV damage and demonstrate that the replication-coupled repair depends on the presence of holC.


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 = $0 )
2025	2024	PORTLAND STATE UNIVERSITY	1600 SW 4TH AVE	PORTLAND	OR	97201	MULTNOMAH	USA	Environmental Health	000	2	10/1/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $221,295 )
2024	2024	PORTLAND STATE UNIVERSITY	1600 SW 4TH AVE	PORTLAND	OR	97201	MULTNOMAH	USA	Environmental Health	000	2	11/30/2023	NON-COMPETING CONTINUATION	$221,295
														Subtotal = $221,295

Issue Date FY: 2023 ( Subtotal = $184,170 )
2023	2023	PORTLAND STATE UNIVERSITY	1600 SW 4TH AVE	PORTLAND	OR	97201	MULTNOMAH	USA	Environmental Health	000	1	11/22/2022	NEW	$184,170
														Subtotal = $184,170

Grand Total All Awards = $405,465

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Replication-Coupled Repair: a mechanism for surviving UV irradiation

Award Number: R21ES034880

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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