Wednesday, January 15, 2025 1/15/2025

Genome-wide analysis of the formation and mutagenesis of atypical UV photoproducts in skin cancer

Award Number: R01ES032814
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract: Exposure to solar ultraviolet (UV) light creates DNA damage that induces high levels of somatic mutations in human skin cancers like melanoma. UV light most commonly causes cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) at dipyrimidine sequences (i.e., TT, TC, CT, and CC). Deamination of cytidines in these lesions or mutagenic bypass leads to their frequent conversion to mutations. As a result, UV- exposed cells and skin cancers are dominated by C to T and CC to TT substitutions in dipyrimidine sequences that collectively constitute a UV mutation signature. Surprisingly, many driver mutations that contribute to melanoma progression have sequence context and substitution characteristics that do not conform to the canonical UV mutation signature. For example, the most common melanoma driver mutation, BRAF V600E, involves a T to A substitution in a GTG sequence context. This difference in mutation characteristics between most UV-induced mutations and melanoma driver mutations has led to the hypothesis that UV light induces melanomagenesis by mechanisms other than the induction of mutations. However, we have recently provided experimental evidence of mutations caused by rare, non-canonical UV lesions in whole genome sequenced yeast and bioinformatics evidence of similar lesions in human clinical skin cancers. These lesions are likely bulky photoproducts formed at TA, CA, and AC dinucleotides. Strikingly, the mutations associated with these atypical UV photoproducts have identical characteristics to many recurrent driver mutations in melanoma, suggesting that these rare lesions may play a significant role in causing skin cancer. The objective of this proposal is to better define the characteristics of atypical UV photoproducts and their contribution to cancer progression. In Aim I, we will utilize CPD and 6-4PP photolyases expressed in yeast to assign UV-induced mutation classes to their corresponding lesion types as well as assess the ability of physiological UVB light to induce mutation classes associated with atypical UV photoproducts in yeast and human cells. In Aim II, we will analyze the genome-wide distribution of atypical TA photoproducts using a novel high throughput sequencing method, called UVDE-seq. We will also characterize the formation of putative CA and AC photoproducts and their contribution to oncogenic BRAF mutations. Finally, Aim III will identify DNA polymerases involved in the error-free and error-prone bypass of TA and AC photoproducts. Successful completion of these aims will provide new insights into the molecular causes of skin cancer, and thereby define a new paradigm of UV mutagenesis that could potentially explain the epidemiological association of acute UV exposure with increased melanoma incidence.


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 = $416,865 )
2025	2025	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Environmental Health	000	5	1/9/2025	NON-COMPETING CONTINUATION	$416,865
														Subtotal = $416,865

Issue Date FY: 2024 ( Subtotal = $416,865 )
2024	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Environmental Health	000	4	1/16/2024	NON-COMPETING CONTINUATION	$416,865
														Subtotal = $416,865

Issue Date FY: 2023 ( Subtotal = $416,865 )
2023	2023	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Environmental Health	000	3	1/24/2023	NON-COMPETING CONTINUATION	$416,865
														Subtotal = $416,865

Issue Date FY: 2022 ( Subtotal = $416,865 )
2022	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Environmental Health	000	2	1/28/2022	NON-COMPETING CONTINUATION	$416,865
														Subtotal = $416,865

Issue Date FY: 2021 ( Subtotal = $416,865 )
2021	2021	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Environmental Health	000	1	3/26/2021	NEW	$416,865
														Subtotal = $416,865

Grand Total All Awards = $2,084,325

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Genome-wide analysis of the formation and mutagenesis of atypical UV photoproducts in skin cancer

Award Number: R01ES032814

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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