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Epitranscriptomic control of ROS

Award Number: R15CA274603
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/24/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Epitranscriptomic control of ROS - Maintenance of the GSH redox cycle is reliant on the activities of selenocysteine-containing GSH metabolizing enzymes which play fundamental roles in chemoprevention. Selenocysteine is the 21st amino acid and does not contain a dedicated codon. Selenocysteine incorporation during translation requires UGA-stop-codon recoding, which uses specifically modified tRNA for accurate decoding. Dynamic changes in tRNA modification are an epitranscriptomic signal because they regulate gene expression post-transcriptionally. We have shown that the stress-induced translation of many selenocysteine containing ROS detoxifying enzymes is dependent on the Alkbh8 tRNA methyltransferase. Alkbh8 enzymatically methylates the uridine wobble base on tRNASelenocysteine to promote UGA-stop codon decoding. We have developed an Alkbh8 deficient mouse and have used molecular, biochemical, and genomic approaches to demonstrate that Alkbh8Def mouse embryonic fibroblasts (MEFs) and some organs display markers of senescence and a senescence gene signature. Using human cells and our new Alkbh8Def/p16-3MR mice we propose to test the hypothesis that senescence occurs in vitro and in vivo because of defective epitranscriptomic signals that controls selenocysteine utilization. To achieve this two aims will: 1. determine if Alkbh8 and other epitranscriptomic writers that limit selenocysteine utilization restrict the senescence program and 2. determine if Alkbh8-deficiency drives senescence in vivo and whether senescence ablation accelerates or tempers pathologies that accompany selenoprotein loss. Our proposal is being submitted with significant preliminary data supporting the idea that Alkbh8 and epitranscriptomic signals are key to chemoprevention by limiting senescent activity.


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: 2024 ( Subtotal = $0 )
2024	2022	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Cancer Biology Research	000	1	4/16/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $296,920 )
2023	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Cancer Biology Research	001	1	7/17/2023	SUPPLEMENT FOR EXPANSION	$296,920
2023	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Cancer Biology Research	000	1	11/30/2022	NEW	$0
														Subtotal = $296,920

Issue Date FY: 2022 ( Subtotal = $459,347 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Cancer Biology Research	000	1	8/24/2022	NEW	$459,347
														Subtotal = $459,347

Grand Total All Awards = $756,267

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Epitranscriptomic control of ROS

Award Number: R15CA274603

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/24/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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