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Regulation of protein multi-functionality by 3 UTRs

Award Number: R35GM144046
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: 02/14/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Regulation of protein multi-functionality by 3 UTRs - Regulation of protein multi-functionality by 3′UTRs SUMMARY Many protein functions are mediated by protein complexes whose formation is often regulated by abundance as higher levels increase the chance to encounter an interaction partner. mRNAs contain a coding region that is translated into protein, but they also contain a 3′ untranslated region (3′UTR). In addition to regulation by abundance, my lab discovered that protein function can be regulated by 3′UTRs as during protein synthesis 3′UTRs mediate protein-protein interactions. 3′UTR-dependent protein complex assembly is mediated by the local translation environment. Each mRNA generates its own translation environment that consists of the proteins bound by the mRNA together with the recruited proteins. As a result, mRNA isoforms with alternative 3′UTRs – that often differ substantially in length – provide drastically different translation environments, and thus encode different protein functions. Currently, thousands of 3′UTR-dependent functions are unknown because they cannot be inferred from canonical protein functions. We have developed a method to systematically identify protein functions mediated by long 3′UTR isoforms of multi-UTR genes using a CRISPR-based approach. We will identify 3′UTRs that mediate so far unknown protein functions involved in the evasion of cell death, in the regulation of migration, and differentiation. We currently know of two ways to achieve 3′UTR-dependent functions. As described above, an mRNA that contains a long 3′UTR can generate its own translation environment. Moreover, mRNAs can use elements in their 3′UTRs to localize to pre-existing translation environments that are formed by phase-separated cytosolic compartments. Within these large cytosolic membraneless organelles the environment is generated by many mRNAs together with their recruited proteins. We discovered such a compartment called TIS granule network. We determined hundreds of enriched mRNAs and observed that usually only half of transcripts with the same 3′UTR localize to TIS granules. This implies that proteins can have alternative functions depending on whether they are translated in the cytosol or in TIS granules. Our goal is to investigate how proteins change their function when translated within TIS granules. To study TIS granule-dependent protein functions, we have engineered cells that are unable to assemble TIS granules. For candidates whose mRNAs are strongly enriched in TIS granules, we are investigating if translation in TIS granules controls the addition of post- translational modifications, the establishment of specific protein complexes, or if it suppresses protein aggregation. If successful, our research will reveal a widespread role of mRNA in the compartmentalization and physical scaffolding during translation. It will show how elements in 3′UTRs contribute to the diversification of protein function. In the long-term, it will facilitate the development of mRNA therapeutics where inclusion of specific 3′UTR elements allows mRNAs to encode proteins with more robust or alternative functions.


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 = $637,200 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	001	4	1/24/2025	NON-COMPETING CONTINUATION	$637,200
2025	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	3	11/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $637,200

Issue Date FY: 2024 ( Subtotal = $708,000 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	001	3	6/27/2024	NON-COMPETING CONTINUATION	$70,800
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	3	12/1/2023	NON-COMPETING CONTINUATION	$637,200
														Subtotal = $708,000

Issue Date FY: 2023 ( Subtotal = $708,000 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	001	2	3/21/2023	NON-COMPETING CONTINUATION	$70,800
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	2	12/9/2022	NON-COMPETING CONTINUATION	$637,200
														Subtotal = $708,000

Issue Date FY: 2022 ( Subtotal = $708,000 )
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Biomedical Research and Research Training	000	1	2/14/2022	NEW	$708,000
														Subtotal = $708,000

Grand Total All Awards = $2,761,200

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Regulation of protein multi-functionality by 3 UTRs

Award Number: R35GM144046

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: 02/14/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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