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The role of heme in the oxidative modification of mRNA

Award Number: F31NS139612
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/26/2025
PERIOD OF PERFORMANCE END DATE: 03/25/2027

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The role of heme in the oxidative modification of mRNA - PROJECT ABSTRACT RNA oxidation is a hallmark of neurodegeneration, and may contribute to the altered gene expression seen in neurodegenerative disease. The major oxidative modification is 8-hydroxyguanosine (8-OHG), which impairs translation and other aspects of RNA function. Reactive oxygen species (ROS), generated by mitochondria through cellular respiration, are the drivers of RNA oxidation. Although ROS is generally thought to nonspecifically modify nucleic acids, microarray analysis of 8-OHG-containing mRNA from Alzheimer's patient samples found that only certain mRNAs underwent oxidation. However, it is currently unclear how ROS can selectively modify specific mRNA. To understand the basis for selective RNA oxidation, I performed an 8-OHG mapping study using antibodies that bind 8-OHG. I found that these antibodies bind to regions which appear to correspond to G-quadruplexes. In vitro studies previously showed that G-quadruplexes can bind heme, converting heme into a highly efficient ROS generator. Based on these prior studies, I asked if heme can bind to cellular mRNA. I developed Heme-seq, a method for mapping heme-binding sites in mRNA, and found that heme-binding sequences are found throughout the transcriptome and correspond to G-quadruplex regions. Additionally, I developed 8-OHG-seq, a new single-nucleotide 8-OHG mapping method, which shows 8-OHG enrichment in G-rich regions consistent with G-quadruplexes. My 8-OHG mapping data supports the idea that 8-OHG is a selective modification. Furthermore, my data suggest that heme binds to G-quadruplex sequences in cellular mRNA, leading to localized ROS generation and RNA oxidation. In order to test this hypothesis, the aims of this project are: Aim 1: To determine the role of heme-binding events on 8-OHG formation in mRNA. I will use small molecules that displace heme from G-quadruplexes to determine if heme must directly contact G-quadruplexes in RNA to catalyze 8-OHG formation. I found that cell stress leads to increased heme binding. I will determine if this increased binding occurs at G-quadruplexes and is associated with formation of new 8- OHG sites. These experiments will address whether heme-binding to G-quadruplexes is the mechanism of specificity for RNA oxidation. Aim 2: To determine the role of cell stress on the folding of heme-binding sites. Cell stress markedly increases the folding of G-quadruplexes in cells. I will map the location of endogenous heme-binding sites induced by serum deprivation and determine if these sequences are G-quadruplexes that fold in response to stress. These aims will provide insights into the role of heme-binding to RNA as a mechanism in RNA oxidation. These studies will also allow me to achieve training goals related to acquiring knowledge and skills in RNA biology, molecular mechanisms related to neurodegeneration, and developing bioinformatic skills, which will help me develop the skills to become an independent investigator.


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 = $50,114 )
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/31/2026	NON-COMPETING CONTINUATION	$576
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/25/2026	NON-COMPETING CONTINUATION	$49,538
														Subtotal = $50,114

Issue Date FY: 2025 ( Subtotal = $49,538 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	8/21/2025	NEW	$564
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	3/25/2025	NEW	$0
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/25/2025	NEW	$48,974
														Subtotal = $49,538

Grand Total All Awards = $99,652

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The role of heme in the oxidative modification of mRNA

Award Number: F31NS139612

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/26/2025

PERIOD OF PERFORMANCE END DATE: 03/25/2027

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