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Mechanisms of Splicing and Retrotransposition

Award Number: R01GM133857
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: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Mechanisms of Splicing and Retrotransposition - PROJECT SUMMARY/ABSTRACT Group II introns are mobile genetic elements that are the likely evolutionary ancestors of both the spliceosome and retrotransposons. RNA splicing and genomic change caused by retrotransposition are fundamental processes common to all eukaryotes. In this proposal, we will examine the mechanisms that drive the function of group II introns, and extend our findings back to their eukaryotic counterparts. Group II introns are comprised of a catalytic RNA core that binds to an intron-encoded protein (IEP) to form a ribonucleoprotein (RNP) complex. Splicing proceeds through two competing reactions: hydrolysis or branching. Introns with a minimal RNA architecture splice exclusively through hydrolysis; however, the addition of the IEP switches the splicing reaction to the branching pathway. This results in the formation of branched lariat RNPs capable of intron mobility. The overall goal of this application is to determine the detailed molecular mechanisms of how intron RNPs form and how these RNPs spread introns to new locations in DNA. This goal will be achieved by combining biochemical and structural biology approaches through the execution of the following two aims. 1) Determine the biochemical mechanism and structural basis for hydrolytic ribozyme activity and protein stimulated lariat-RNP formation. This will allow a detailed comparison of the active sites of a pure RNA self-splicing intron, self-splicing intron RNP and the spliceosomal RNP, providing the first insights into how the splicing machinery evolved from a pure ribozyme to the protein-RNA molecular machine responsible for processing almost all mRNA transcripts in the human transcriptome. 2) Determination of the biochemical mechanism and structural basis for intron mobility into DNA. These experiments will provide systematic mechanistic insights into the interplay between the intron and the IEP reverse transcriptase that complete the intron integration reaction into new DNA locations.


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 = -$23,856 )
2026	2023	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Biomedical Research and Research Training	000	5	1/16/2026	NON-COMPETING CONTINUATION	-$23,856
														Subtotal = -$23,856

Issue Date FY: 2023 ( Subtotal = $319,200 )
2023	2023	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Biomedical Research and Research Training	000	5	5/16/2023	NON-COMPETING CONTINUATION	$319,200
														Subtotal = $319,200

Issue Date FY: 2022 ( Subtotal = $319,200 )
2022	2022	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE	MORGANTOWN	WV	26506	MONONGALIA	USA	Biomedical Research and Research Training	000	4	5/24/2022	NON-COMPETING CONTINUATION	$319,200
														Subtotal = $319,200

Issue Date FY: 2021 ( Subtotal = $319,200 )
2021	2021	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE	MORGANTOWN	WV	26506	MONONGALIA	USA	Biomedical Research and Research Training	000	3	5/18/2021	NON-COMPETING CONTINUATION	$319,200
														Subtotal = $319,200

Issue Date FY: 2020 ( Subtotal = $319,200 )
2020	2020	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE	MORGANTOWN	WV	26506	MONONGALIA	USA	Biomedical Research and Research Training	000	2	5/1/2020	NON-COMPETING CONTINUATION	$319,200
														Subtotal = $319,200

Issue Date FY: 2019 ( Subtotal = $319,200 )
2019	2019	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE	MORGANTOWN	WV	26506	MONONGALIA	USA	Biomedical Research and Research Training	000	1	7/30/2019	NEW	$319,200
														Subtotal = $319,200

Grand Total All Awards = $1,572,144

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Mechanisms of Splicing and Retrotransposition

Award Number: R01GM133857

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: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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