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Translational Control by Human Pumilio Proteins

Award Number: R01GM150468
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: 08/18/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Translational Control by Human Pumilio Proteins - Project Summary The human RNA-binding proteins, PUM1 and PUM2, are essential for mammalian development and their dysfunction is linked to multiple human diseases including developmental defects, neurological disorders, infertility, cancers, and mitochondrial dysfunction. These important functions compel our overall objective to discover how PUM1&2 control the flow of genetic information from gene to mRNA to protein and to identify the full repertoire of genes that they regulate. PUM1&2 bind to thousands of mRNAs in human cells by recognizing an RNA sequence called the Pumilio Response Element (PRE). Previous research showed that PUM1&2 promote degradation of hundreds of these PRE-containing mRNAs by recruiting RNA decay enzymes. It is now clear, however, that this mechanism represents only one type of PUM-mediated regulatory outcome. Thousands of mRNAs are bound by PUM1&2 but are not degraded. Therefore, it is now necessary to determine how PUM1&2 control the fate of all target mRNAs. The resulting data will provide a comprehensive view of their regulatory roles in biology and pathogenesis. We propose that human PUM1&2 repress many target mRNAs by inhibiting the process of translation. This hypothesis is supported by multiple examples of genes that are repressed by PUM1&2 at the level of protein abundance in the absence of mRNA degradation. The mechanism and prevalence of this translational inhibition is unknown. In addition, our data indicate that for some genes PUM-mediated translational inhibition can synergize with RNA degradation to regulate gene expression to a larger extent than either process alone. RNA molecules form structures that influence their function and fate. While biochemical evidence indicates that RNA structure can modulate PUM-PRE interactions, its effect in vivo remains unknown. In fact, there is an overall lack of RNA structural information of mRNAs in human cells that limits our understanding of how that structure influences gene regulation by RNA-binding proteins like PUM1&2. The proposed research seeks to determine how PUM1&2 inhibit translation and to identify the translational regulatory factors that are necessary for PUM1&2 activity. The structure of human mRNAs will be determined and its effect on PUM-mRNA interactions and regulatory network will be analyzed. By integrating this new data with existing knowledge of which mRNAs are bound and degraded by PUM1&2, we will develop a comprehensive understanding of this key genetic regulatory network. Discovery of the full regulatory network of PUM1&2 will provide new insights into how they control gene expression to regulate normal biological processes. Moreover, this knowledge will help elucidate how their dysfunction leads to diseases such as neurodegeneration and cancer.


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 = $379,675 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Biomedical Research and Research Training	000	3	6/3/2025	NON-COMPETING CONTINUATION	$379,675
														Subtotal = $379,675

Issue Date FY: 2024 ( Subtotal = $551,573 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	001	2	8/20/2024	SUPPLEMENT FOR EXPANSION	$171,898
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	2	6/25/2024	NON-COMPETING CONTINUATION	$379,675
														Subtotal = $551,573

Issue Date FY: 2023 ( Subtotal = $379,675 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Biomedical Research and Research Training	000	1	8/18/2023	NEW	$379,675
														Subtotal = $379,675

Grand Total All Awards = $1,310,923

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Translational Control by Human Pumilio Proteins

Award Number: R01GM150468

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: 08/18/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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