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Selectivity and regulation of mRNA demethylation by iron-dependent dioxygenases

Award Number: R35GM143000
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Selectivity and regulation of mRNA demethylation by iron-dependent dioxygenases - TITLE: Selectivity and regulation of mRNA demethylation by iron-dependent dioxygenases ABSTRACT: The long-term goals of this research program are to (1) define the structural and molecular mechanisms that control the selectivity and function of RNA demethylase enzymes, (2) develop new chemical tools to monitor RNA demethylation in cells, and (3) understand how the key cofactor ascorbic acid interacts with RNA demethylases and other iron-dependent dioxygenase family members to regulate their activity. Methyl modifications on mRNA tune transcript function, are essential for mammalian cell fate decisions, and play important roles in the progression of many human cancers. The iron-dependent dioxygenase enzymes FTO and AlkBH5 act as ‘erasers’ of highly abundant N6-methyladenosine (m6A) modifications found in the mRNA body and, in the case of FTO, N6,2’-O-dimethyladenosine (m6Am) modifications found on the 5’ mRNA cap. These RNA demethylases are overexpressed in cancers including glioblastoma and acute myeloid leukemia, where increased demethylation activity and reduced methyl modification levels promote tumorigenesis and cancer progression. Despite these clear links to human disease, we currently have a poor understanding of how FTO and AlkBH5 recognize their biological substrates, which mRNA transcripts are targeted for demethylation, and how demethylation influences mRNA function. Furthermore, FTO and AlkBH5 belong to the non-heme iron(II) and -ketoglutarate-dependent family of dioxygenases that require ascorbic acid (vitamin C) as a cofactor for efficient activity, but we have almost no structure-level insights into how ascorbic acid interacts with this diverse family of enzymes and how this physical interaction may potentiate dioxygenase activity in cells. This proposal combines approaches from biochemistry, structural biology, chemical biology, bioinorganic chemistry, and cell biology to determine the structural basis for RNA demethylase selectivity, develop novel probes to map demethylation targets across the transcriptome, and quantify and visualize the dioxygenase-ascorbic acid interaction to understand how this cofactor regulates enzymatic activity. The results from these proposed studies will significantly enhance our understanding of how cellular mRNA demethylation is regulated in cells and pave the way for therapeutics that target demethylation pathways in challenging cancers such as glioblastoma.


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 = $390,771 )
2025	2025	UNIVERSITY OF DELAWARE	550 S COLLEGE AVE	NEWARK	DE	19713	NEW CASTLE	USA	Biomedical Research and Research Training	000	5	5/20/2025	NON-COMPETING CONTINUATION	$390,771
														Subtotal = $390,771

Issue Date FY: 2024 ( Subtotal = $391,040 )
2024	2024	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Biomedical Research and Research Training	000	4	6/21/2024	NON-COMPETING CONTINUATION	$391,040
														Subtotal = $391,040

Issue Date FY: 2023 ( Subtotal = $486,374 )
2023	2023	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Biomedical Research and Research Training	001	3	6/22/2023	SUPPLEMENT FOR EXPANSION	$95,073
2023	2023	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Biomedical Research and Research Training	000	3	4/28/2023	NON-COMPETING CONTINUATION	$391,301
														Subtotal = $486,374

Issue Date FY: 2022 ( Subtotal = $391,554 )
2022	2022	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Biomedical Research and Research Training	000	2	5/11/2022	NON-COMPETING CONTINUATION	$391,554
														Subtotal = $391,554

Issue Date FY: 2021 ( Subtotal = $391,800 )
2021	2021	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Biomedical Research and Research Training	000	1	6/25/2021	NEW	$391,800
														Subtotal = $391,800

Grand Total All Awards = $2,051,539

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Selectivity and regulation of mRNA demethylation by iron-dependent dioxygenases

Award Number: R35GM143000

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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