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Watching cooperative interactions between base and nucleotide excision repair proteins

Award Number: R35ES031638
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: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Watching cooperative interactions between base and nucleotide excision repair proteins - Title: Watching cooperative interactions between base and nucleotide excision repair proteins. PI: Bennett Van Houten, PhD Abstract/Summary This highly innovative project seeks to answer several fundamental questions regarding how DNA repair proteins work to protect the human genome from environmentally-induced DNA damage. This project uses an integrated approach combining biochemistry, single molecule analysis and highly innovative chemoptogenetic cell biology tools to study with high temporal and spatial resolution molecular hand-offs during DNA repair. We posit that key nucleotide excision repair proteins including UV-DDB, XPA, and XPC-RAD23B work in a dynamic way with specific base excision repair proteins to process oxidized bases in the context of chromatin. Specially, we will follow purified DNA repair proteins and/or proteins labeled from nuclear extracts as they interact at sites of damage on naked DNA and chromatinized DNA using a DNA tightrope optical platform. Building on preliminary data and premise that UV-DDB can change the register of specific lesions in the context of the nucleosome, we will test the paradigm shifting hypothesis that UV-DDB working in concert with other NER proteins is a general damage sensor and can stimulate APE1 and 11 mammalian DNA glycosylases activities on their respective oxidized DNA substrates. This project will develop and validate new genomic tools to place 8-oxoG adducts at defined sites throughout the genome to assess the how chromatin structure and chromatin remodelers effects repair. We will also develop and use several high-resolution fluorescent approaches including single particle tracking protocols (based on Halo- and SNAP-tags) to watch individual repair proteins arrive and process damage sites in real-time in living cells. Finally, we posit that UV-DDB and XPC-RAD23B work with thymine DNA glycosylase to alter methylation patterns in cells and ultimately change gene expression profiles. Together these approaches will give an unprecedented view of the complex process of DNA damage processing during repair and answer several key questions regarding damage recognition that have been intractable in the absence of super-resolution approaches. Completion of this project will have a long and lasting impact on the field.


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 = $906,257 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Environmental Health	000	7	2/9/2026	NON-COMPETING CONTINUATION	$906,257
														Subtotal = $906,257

Issue Date FY: 2025 ( Subtotal = $906,257 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Environmental Health	001	6	9/26/2025	NON-COMPETING CONTINUATION	$0
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Environmental Health	000	6	3/10/2025	NON-COMPETING CONTINUATION	$906,257
														Subtotal = $906,257

Issue Date FY: 2024 ( Subtotal = $906,257 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Environmental Health	001	5	2/29/2024	NON-COMPETING CONTINUATION	$906,257
2024	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Environmental Health	000	4	2/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $906,257

Issue Date FY: 2023 ( Subtotal = $919,375 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Environmental Health	001	4	5/2/2023	SUPPLEMENT FOR EXPANSION	$13,118
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Environmental Health	000	4	3/1/2023	NON-COMPETING CONTINUATION	$906,257
														Subtotal = $919,375

Issue Date FY: 2022 ( Subtotal = $906,257 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Environmental Health	000	3	3/2/2022	NON-COMPETING CONTINUATION	$906,257
														Subtotal = $906,257

Issue Date FY: 2021 ( Subtotal = $906,257 )
2021	2021	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Environmental Health	000	2	2/17/2021	NON-COMPETING CONTINUATION	$906,257
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Environmental Health	001	2	9/21/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $906,257

Issue Date FY: 2020 ( Subtotal = $751,226 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Environmental Health	000	1	5/26/2020	NEW	$751,226
														Subtotal = $751,226

Grand Total All Awards = $6,201,886

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Watching cooperative interactions between base and nucleotide excision repair proteins

Award Number: R35ES031638

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: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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