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Eukaryotic RNA NAD capping and deNADding

Award Number: R01GM126488
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: 02/27/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Eukaryotic RNA NAD capping and deNADding - RNA 5′ end capping provides a layer of “epitranscriptomic” regulation, influencing numerous aspects of RNA fate, including stability, processing, localization and translatability. Furthermore, enzymes that remove RNA 5′ end caps play critical roles in modulating these processes. Recently, a previously unknown form of RNA 5'-end capping has been identified in bacterial, yeast, and human cells. In this new form of RNA capping, the metabolite nicotinamide adenine dinucleotide (NAD) is added at the RNA 5′ end. In contrast to 7- methylguanylate (m7G) caps, which are added to mRNAs by a complex that associates with eukaryotic RNA polymerase II (RNAP II), NAD caps are primarily added by RNAP itself in bacteria and eukaryotic nuclear and mitochondrial transcripts. Thus, unlike m7G capping, which is observed in eukaryotes and certain eukaryotic viruses, NAD capping is likely to occur in most, if not all, organisms. Our recently published work along with our unpublished preliminary data, indicates that NAD capping targets mammalian RNAs for rapid decay. In addition, we have shown eukaryotic cells possess several enzymes capable of removing NAD caps and, furthermore, that the cellular functions of these “deNADding” enzymes are most evident during metabolic stress. An overall theme emerging from our data is that addition and removal of NAD caps play critical roles in mitochondrial function where NAD-capped mitochondrial-encoded transcripts and nuclear transcripts encoding mitochondrial proteins are modulated by NAD caps. To decipher the interplay between cellular assimilation of NAD and RNA metabolism we will define the functional role(s) of NAD caps and deNADding enzymes in both budding yeast and mammalian cells. The first aim will investigate the hypothesis that NAD capping of mitochondrial RNA plays a key role in maintaining NAD homeostasis with the NAD cap serving as a reservoir to sequester and release free NAD for proper mitochondrial energetics. The second aim will investigate the impact of NAD capping on nuclear encoded RNA and, in particular, explores the hypothesis that NAD capping in budding yeast provides a mechanism for the targeted decay of RNAs in response to nutrient stress. The third aim will determine how the NAD capping and deNADding of mammalian nuclear mRNAs encoding mitochondrial proteins contributes to mitochondrial function upon cellular stress and whether perturbation of the deNADding of these mRNAs contributes to mitochondrial dysfunction associated with aging. The proposed studies will provide new insight in an emerging area of RNA biology, post- transcriptional regulation in cellular metabolism and, furthermore, may provide a mechanistic framework for developing new approaches to control gene expression in normal and disease states.


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	2023	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	6	9/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $398,580 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	002	6	5/22/2023	NON-COMPETING CONTINUATION	$0
2023	2023	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	003	6	7/31/2023	SUPPLEMENT FOR EXPANSION	$33,494
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	6	3/29/2023	NON-COMPETING CONTINUATION	$365,086
2023	2021	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	4	11/7/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $398,580

Issue Date FY: 2022 ( Subtotal = $365,086 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	5	5/16/2022	COMPETING CONTINUATION	$365,086
2022	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	4	5/9/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $365,086

Issue Date FY: 2021 ( Subtotal = $349,936 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	4	3/19/2021	NON-COMPETING CONTINUATION	$34,994
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	4	1/18/2021	NON-COMPETING CONTINUATION	$314,942
														Subtotal = $349,936

Issue Date FY: 2020 ( Subtotal = $349,936 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	3	1/15/2020	NON-COMPETING CONTINUATION	$349,936
														Subtotal = $349,936

Issue Date FY: 2019 ( Subtotal = $417,829 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	2	7/24/2019	SUPPLEMENT FOR EXPANSION	$67,893
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	2	1/24/2019	NON-COMPETING CONTINUATION	$349,936
														Subtotal = $417,829

Issue Date FY: 2018 ( Subtotal = $500,403 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	2/27/2018	NEW	$367,200
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	1	8/13/2018	SUPPLEMENT FOR EXPANSION	$133,203
														Subtotal = $500,403

Grand Total All Awards = $2,381,770

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Eukaryotic RNA NAD capping and deNADding

Award Number: R01GM126488

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: 02/27/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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