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Characterization of a Model System to Advance Triple-Stranded RNA Biology

Award Number: R35GM133696
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: 07/31/2025

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Characterization of a Model System to Advance Triple-Stranded RNA Biology - Project Summary Excitement about RNA triple helices has grown rapidly in recent years due to their newfound biological roles in telomere synthesis, pre-mRNA splicing, protecting cancer-promoting RNAs from degradation and now genome editing. Therefore, the discovery and characterization of more RNA triple helices is a pre-requisite to elucidating other fundamental biological processes mediated by triple-helical structures. As only 11 naturally occurring RNA triple helices have been validated to date and more are predicted, there is a clear need for the development of molecular tools to determine the global landscape of RNA triple helices throughout nature. Herein, the principal investigator proposes to characterize the MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) RNA triple helix and its protein-binding partner, METTL16 (methyltransferase-like protein 16). The MALAT1 triple helix and METTL16 complex is the first putative triple-stranded ribonucleoprotein complex, thereby representing a unique opportunity to provide unprecedented insights into triple-stranded RNA biology. In Research Areas #1 and #2, the structural basis of how METTL16 and small molecules specifically recognize and interact with the MALAT1 triple helix will be determined for the first time using a combination of X-ray crystallography and biochemical methods. This effort will generate the foundational knowledge needed to develop novel experimental tools for the global discovery of more RNA triple helices. Moreover, the discovery of an entirely new class of proteins, that is triple-stranded RNA-binding proteins, is anticipated. In Research Areas #3 and #4, the biological function of human METTL16 as a putative triple-stranded RNA-binding protein will be investigated using both in vitro and cell-based biochemical assays. This functional investigation will focus on the roles of the METTL16-MALAT1 triple helix complex as well as broader roles for METTL16 and its RNA-binding partners in the context of Miller-Dieker Syndrome, a rare neurodegenerative disease in which one chromosomal copy of the mettl16 gene is deleted. Thus, METTL16 and the MALAT1 triple helix represent a model system with high potential to transform the field of triple- stranded RNA biology, opening unforeseen areas of biomedical investigation.


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 = -$127 )
2026	2023	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	5	4/2/2026	NON-COMPETING CONTINUATION	-$127
														Subtotal = -$127

Issue Date FY: 2023 ( Subtotal = $386,250 )
2023	2023	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	5	7/25/2023	NON-COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2022 ( Subtotal = $386,250 )
2022	2022	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	4	7/21/2022	NON-COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2021 ( Subtotal = $386,250 )
2021	2021	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	3	7/28/2021	NON-COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2020 ( Subtotal = $386,250 )
2020	2020	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	2	7/6/2020	NON-COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2019 ( Subtotal = $386,250 )
2019	2019	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	1	8/1/2019	NEW	$386,250
														Subtotal = $386,250

Grand Total All Awards = $1,931,123

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Characterization of a Model System to Advance Triple-Stranded RNA Biology

Award Number: R35GM133696

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: 07/31/2025

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