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Environmental DNA Lesions and Mutagenesis: Molecular Mechanisms of Lesion Recognition for Repair and Polymerase Bypass

Award Number: R01ES025987
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: 06/01/2016
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Environmental DNA Lesions and Mutagenesis: Molecular Mechanisms of Lesion Recognition for Repair and Polymerase Bypass - PROJECT SUMMARY The human genome is constantly attacked from sources that include environmental pollutants, other exogenous origins that include drug treatment, endogenous reactive oxygen species, and UV light. Among the lesions/adducts are ones derived from polycyclic aromatic compounds, found at toxic waste dumps, superfund sites, in our air, food and water. The resulting DNA lesions cause mutations that lead to cancer. However, not all DNA lesions are equally carcinogenic, as their mutagenic propensities vary: a cascade of processes determines whether they are repaired, or survive for mutagenic or error-free bypass by DNA polymerases. Human nucleotide excision repair (NER) is a key mechanism for removal of many such DNA lesions. The vital importance of NER is demonstrated in the devastating human disorder xeroderma pigmentosum, caused by mutations in NER genes. Notably, some lesions are rapidly repaired, some slowly, and some are resistant and thus particularly genotoxic, a phenomenon that is poorly understood. Likewise, there is a gap in our understanding of the mechanisms underlying DNA lesion bypass by polymerases that can lead to a mutagenic or error-free outcome. The objective of this project is to provide mechanistic insights into the puzzling variability of DNA lesion mutagenicity, focusing on the key steps of lesion recognition for repair and mutagenic bypass, to yield integrated new molecular and dynamic understanding of lesion mutagenic proclivity in unprecedented atomistic detail, using molecular dynamics simulations. Our overall hypothesis is that the structure of the lesion and its base sequence context determine its overall mutagenic propensity. In Aim 1, we will utilize a selected set of DNA lesions/adducts whose structures differ greatly in size and shape, placed in differing sequence contexts, to determine structural, energetic and dynamic characteristics of the lesion-containing DNAs as they bind to Rad4/XPC, the yeast homolog of the human XPC lesion recognition protein. We will reveal how those that bind for productive recognition leading to excision differ from those that fail to do so. In Aim 2 we will determine how the human XPD helicase in TFIIH, that verifies the presence of lesions for NER by stalling, processes lesions of different sizes and shapes, and how XPD mutations that cause human disease inhibit XPD’s function. In Aim 3 we will determine how differing lesion structures in varying nucleosomal positions impose different distortions on the nucleosome and how selected histone acetylations modulate these distortions, to promote or inhibit access for repair. In Aim 4 we investigate endogenous and exogenous DNA peptide crosslink lesions, to determine how selected DNA bypass polymerases process them error-free or mutagenically, in differing DNA sequence contexts. Focusing on the most mutagenic lesions, our work will facilitate identification of appropriate biomarkers for determining risk of developing cancer, advance design of chemotherapy drugs that are less repaired, and yield a predictive tool to identify mutational hotspot sequences induced by different lesions in human tumors.


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 = $0 )
2026	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S FL 11	NEW YORK	NY	10012	NEW YORK	USA	Environmental Health	000	44	2/2/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $356,435 )
2025	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Environmental Health	000	44	5/9/2025	NON-COMPETING CONTINUATION	$356,435
														Subtotal = $356,435

Issue Date FY: 2024 ( Subtotal = $356,435 )
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Environmental Health	000	43	4/23/2024	NON-COMPETING CONTINUATION	$356,435
														Subtotal = $356,435

Issue Date FY: 2023 ( Subtotal = $356,066 )
2023	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Environmental Health	000	42	4/21/2023	NON-COMPETING CONTINUATION	$356,066
														Subtotal = $356,066

Issue Date FY: 2022 ( Subtotal = $371,959 )
2022	2022	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Environmental Health	002	41	4/22/2022	NON-COMPETING CONTINUATION	$371,959
2022	2021	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Environmental Health	001	40	11/27/2021	COMPETING CONTINUATION	$611
2022	2020	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Environmental Health	000	39	11/27/2021	NON-COMPETING CONTINUATION	-$611
														Subtotal = $371,959

Issue Date FY: 2021 ( Subtotal = $367,900 )
2021	2021	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Environmental Health	001	40	8/2/2021	COMPETING CONTINUATION	$367,900
2021	2020	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Environmental Health	000	39	7/23/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $367,900

Issue Date FY: 2020 ( Subtotal = $356,625 )
2020	2020	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Environmental Health	000	39	5/21/2020	NON-COMPETING CONTINUATION	$356,625
														Subtotal = $356,625

Issue Date FY: 2019 ( Subtotal = $356,625 )
2019	2019	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Environmental Health	000	38	5/29/2019	NON-COMPETING CONTINUATION	$356,625
														Subtotal = $356,625

Issue Date FY: 2018 ( Subtotal = $356,625 )
2018	2018	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Environmental Health	000	37	5/31/2018	NON-COMPETING CONTINUATION	$356,625
														Subtotal = $356,625

Issue Date FY: 2017 ( Subtotal = $356,625 )
2017	2017	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Environmental Health	000	36	5/26/2017	NON-COMPETING CONTINUATION	$356,625
														Subtotal = $356,625

Issue Date FY: 2016 ( Subtotal = $346,095 )
2016	2016	NEW YORK UNIVERSITY	SPONSORED PGMS ACCOUNTING	NEW YORK	NY	10003	NEW YORK	USA	Environmental Health	000	35	5/19/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$346,095
														Subtotal = $346,095

Grand Total All Awards = $3,581,390

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Environmental DNA Lesions and Mutagenesis: Molecular Mechanisms of Lesion Recognition for Repair and Polymerase Bypass

Award Number: R01ES025987

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: 06/01/2016

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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