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Mechanistic studies of nucleic acid enzymes involved in DNA replication, transcription, and innate immunity

Award Number: R35GM118086
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary The overarching goal of our research is to understand the mechanisms of helicases and polymerases in processes such as viral RNA recognition, DNA transcription, and replication. The unifying approach is the quantitative characterization of the enzymatic reactions using rigorous biochemical and biophysical methods such as transient state kinetics, single-molecule kinetics, computational kinetic modeling, and cryo-electron microscopy. The integration of structural and functional studies allows the development of a complete mechanistic picture. In project 1, we are studying viral RNA recognition by RIG-I like receptors which are helicases serving as the first responders of viral RNA infections. The RIG-I like receptors recognize pathogen- associated molecular patterns on viral genomes and replication intermediates and respond by triggering an immune response to create an antiviral state. Our research focuses on understanding the mechanisms of RNA recognition and ATPase/helicase functions of RIG-I like receptors using biochemical, structural, and cell- signaling assays. We are elucidating the intrinsic mechanisms in RIG-I that enable self versus non-self recognition and developing new strategies to understand how they are activated and regulated. In project 2, we are studying the mechanism and regulation of mitochondrial DNA transcription catalyzed by RNA polymerases that resemble phage T7 but regulated by transcription factors. Transcription initiation and transition into elongation are key stages that are regulated by transcription factors. We are using cryo-electron microscopy, and ensemble/single-molecule kinetics to elucidate the structure and dynamics at these stages of transcription using in vitro reconstituted yeast and human mitochondrial RNA polymerases. In project 3, we are studying the mechanism of DNA replication by phage T7 and human mitochondrial replisomes. We study how helicase and polymerase work together to catalyze strand-displacement DNA synthesis, in particular, how they are energetically coupled. We are studying the mechanism of DNA synthesis by mitochondrial DNA polymerase to understand the role of helicase, Twinkle, and mitochondrial single-strand binding protein. An in- depth understanding of the enzymatic mechanisms is critically necessary to understand mitochondrial DNA deletions caused by defects in helicase and polymerase. This research will provide the mechanistic framework to quantitatively model the reactions of replication, transcription, and pathogen recognition that will guide in the development of therapies for viral infections, cancer, mitochondrial diseases.


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 = $828,047 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Biomedical Research and Research Training	002	9	5/1/2024	NON-COMPETING CONTINUATION	$828,047
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Biomedical Research and Research Training	001	8	12/19/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$91,307
2024	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	7	12/19/2023	NON-COMPETING CONTINUATION	-$91,307
														Subtotal = $828,047

Issue Date FY: 2023 ( Subtotal = $828,290 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Biomedical Research and Research Training	001	8	4/17/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$828,290
2023	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	7	4/14/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $828,290

Issue Date FY: 2022 ( Subtotal = $828,290 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	7	6/9/2022	NON-COMPETING CONTINUATION	$828,290
														Subtotal = $828,290

Issue Date FY: 2021 ( Subtotal = $827,460 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	005	6	9/5/2021	COMPETING CONTINUATION	$254,561
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	002	6	4/22/2021	COMPETING CONTINUATION	$827,460
2021	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	004	5	9/5/2021	SUPPLEMENT FOR EXPANSION	-$91,141
2021	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	5	4/14/2021	NON-COMPETING CONTINUATION	$0
2021	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	003	5	9/5/2021	NON-COMPETING CONTINUATION	-$163,420
2021	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	001	5	4/14/2021	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $827,460

Issue Date FY: 2020 ( Subtotal = $923,567 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	5	4/13/2020	NON-COMPETING CONTINUATION	$832,426
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	001	5	8/26/2020	SUPPLEMENT FOR EXPANSION	$91,141
														Subtotal = $923,567

Issue Date FY: 2019 ( Subtotal = $832,426 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	4	4/12/2019	NON-COMPETING CONTINUATION	$832,426
														Subtotal = $832,426

Issue Date FY: 2018 ( Subtotal = $816,553 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	3	4/20/2018	NON-COMPETING CONTINUATION	$816,553
														Subtotal = $816,553

Issue Date FY: 2017 ( Subtotal = $714,913 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	2	4/11/2017	NON-COMPETING CONTINUATION	$577,771
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	002	2	8/24/2017	SUPPLEMENT FOR EXPANSION	$72,946
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	001	2	6/15/2017	NON-COMPETING CONTINUATION	$64,196
														Subtotal = $714,913

Issue Date FY: 2016 ( Subtotal = $491,860 )
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	4/25/2016	NEW	$491,860
														Subtotal = $491,860

Grand Total All Awards = $7,091,406

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Mechanistic studies of nucleic acid enzymes involved in DNA replication, transcription, and innate immunity

Award Number: R35GM118086

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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