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New Paradigms for the molecular basis of RNA polymerase I transcription

Award Number: R01GM141033
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: 03/05/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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New Paradigms for the molecular basis of RNA polymerase I transcription - Project Summary Eukaryotic RNA polymerase I (Pol I) transcribes ribosomal RNA, a key component of ribosomes. Pol I transcription accounts for the majority of the total RNA in cells, and its upregulation in human cells is a hallmark of cancer while its downregulation is a hallmark of several developmental disorders. Pol I transcription is understudied compared to transcription by Pol II and even Pol III. Our preliminary work suggests fundamental differences between Pol I and Pols II and III that are the basis for this proposal. Our broad long-term objectives are to determine the molecular mechanism of Pol I transcription and how its dysregulation leads to cancer and developmental disorders. There are major gaps in our understanding of (1) the structural organization and architecture of Pol I transcription complexes; (2) the mechanism for how Pol I initiation factors interact with rDNA, which encodes ribosomal RNA; and (3) the molecular function of several key Pol I transcription factors in the activation process. The first rationale for this work is that determining the mechanism and regulation of Pol I transcription will form the molecular basis for understanding how Pol I defects lead to human disease. Our central hypothesis is that Pol I factors use a unique mechanism to carry out transcription and their structure and function is different from the mechanisms governing Pol II and III transcription. The second rationale is that understanding the Pol I transcription mechanism at the most basic and fundamental levels will translate to a better understanding of the connection between Pol I and cancer, leading to new cancer therapeutic strategies. Our proposed research will use a conceptually and technically innovative cross-organismal and interdisciplinary approach that employs a combination of bioinformatic, computational, molecular, biochemical, genetic, genomic, proteomic, and structural methods in the yeast and human cells. Guided by strong preliminary studies, we will test two specific aims: (1) Determine the unique “coactivator” role of TATA-binding protein (TBP) in Pol I transcription, and (2) Determine the mechanism of Pol I transcription activation. To accomplish these aims, we will use well-established and complementary approaches to identify and map novel Pol I interactions in their native context. We will complement these studies with structural modeling in combination with molecular, genetic, and biochemical functional assays to identify Pol I factor functions conserved from yeast to humans. The proposed research is significant because it will lead to a detailed description of the Pol I transcription mechanism and will provide a conceptual framework for understanding the link between Pol I and human disease. Ultimately, this work will illuminate new avenues for diagnosis, potential interventions, and the development of therapies targeting these novel protein-protein and protein-DNA interactions.


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 = $328,762 )
2025	2025	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	001	5	2/19/2025	NON-COMPETING CONTINUATION	$306,180
2025	2025	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	000	4	11/25/2024	SUPPLEMENT FOR EXPANSION	$22,582
														Subtotal = $328,762

Issue Date FY: 2024 ( Subtotal = $462,650 )
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	000	4	2/27/2024	NON-COMPETING CONTINUATION	$306,180
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	002	4	7/24/2024	NON-COMPETING CONTINUATION	$34,020
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	001	4	5/20/2024	SUPPLEMENT FOR EXPANSION	$122,450
														Subtotal = $462,650

Issue Date FY: 2023 ( Subtotal = $351,258 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	002	3	5/22/2023	SUPPLEMENT FOR EXPANSION	$11,058
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	001	3	4/13/2023	NON-COMPETING CONTINUATION	$34,020
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	000	3	1/27/2023	NON-COMPETING CONTINUATION	$306,180
														Subtotal = $351,258

Issue Date FY: 2022 ( Subtotal = $430,223 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	002	2	8/3/2022	NON-COMPETING CONTINUATION	$34,020
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	000	2	2/3/2022	NON-COMPETING CONTINUATION	$306,180
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	001	2	5/12/2022	SUPPLEMENT FOR EXPANSION	$90,023
														Subtotal = $430,223

Issue Date FY: 2021 ( Subtotal = $340,200 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	000	1	3/4/2021	NEW	$340,200
														Subtotal = $340,200

Grand Total All Awards = $1,913,093

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New Paradigms for the molecular basis of RNA polymerase I transcription

Award Number: R01GM141033

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: 03/05/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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