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Implication of histone H4 LRS mutations in translesion synthesis and UV mutagenesis

Award Number: R03ES033789
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: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Implication of histone H4 LRS mutations in translesion synthesis and UV mutagenesis - PROJECT SUMMARY/ABSTRACT The solar ultraviolet (UV) is the most pervasive carcinogen in our natural environment. Translesion synthesis (TLS) is a DNA damage tolerance mechanism that utilizes specialized DNA polymerases to bypass UV and other replication-blocking lesions, often leading to mutagenesis. Somatic mutations resulting from TLS of unrepaired UV lesions are the major causes for essentially all skin cancers, especially melanoma. Indeed, melanoma building associated with UV exposure has the highest number of somatic mutations per tumor. The basic block of eukaryotic chromatin is the nucleosome, which consists of DNA wrapping around a histone octamer comprised of one (H3-H4)2 tetramer and two H2A-H2B dimers. PCNA is a hub protein that mediates DNA replication, replication-coupled nucleosome assembly, and TLS. LRS isa nucleosome domain composed of mutations in S. cerevisiae. The certain residues of histones H3 and H4. H4 LRS mutations mostly or entirely embedded in the nucleosome, but not those We identified multiple UV sensitive or resistant histone H4 LRS on the nucleosome surface, attenuate TLS and UV mutagenesis. The TLS-deficient H4 LRS mutations globally destabilize chromatin structure, but do not affect PCNA ubiquitination, a modification known to be required for TLS, indicating that they affect a TLS step downstream of the PCNA modification. To date, studies on how chromatin structures modulate TLS and mutagenesis have been scarce, if not nonexistent. It has been generally assumed that chromatin organization passively inhibits TLS. Our finding challenges the assumption and indicates that a chromatin feature in the LRS is required for efficient TLS. Our finding offers an important clue for unraveling the long-standing enigma of how chromatin structures modulate TLS and mutagenesis. The goal of this project is to elucidate how the histone H4 LRS mutations attenuate TLS and UV mutagenesis. We hypothesize that the TLS-deficient H4 LRS mutations compromise replication-coupled nucleosome assembly and post-assembly nucleosome stability upstream of DNA lesions, thereby attenuating the retention of PCNA and the recruitment of TLS polymerases. We will determine how the TLS-deficient histone H4 LRS mutations 1) affect nucleosome occupancies upstream of UV lesions, 2) affect the retention of PCNA and the recruitment of TLS polymerases, and 3) functionally interact with histone H3-H4 chaperones, which act at different steps of the replication-coupled nucleosome assembly process, to affect TLS and UV mutagenesis. Findings from the project will form the basis for future elucidation of how nucleosome features crosstalk with histone chaperones and local genomic features to modulate the genomic landscape of TLS and mutagenesis. Also, the study may be informative for identifying new targets for the treatment and/or prevention of cancers, especially melanoma.


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 = -$184 )
2026	2023	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Environmental Health	000	2	4/7/2026	NON-COMPETING CONTINUATION	-$184
														Subtotal = -$184

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Environmental Health	000	2	12/23/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $71,216 )
2023	2023	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Environmental Health	000	2	11/23/2022	NON-COMPETING CONTINUATION	$71,216
														Subtotal = $71,216

Issue Date FY: 2022 ( Subtotal = $71,216 )
2022	2022	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Environmental Health	000	1	11/25/2021	NEW	$71,216
														Subtotal = $71,216

Grand Total All Awards = $142,248

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Implication of histone H4 LRS mutations in translesion synthesis and UV mutagenesis

Award Number: R03ES033789

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: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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