# Regulation of protein multi-functionality by 3 UTRs

> **NIH NIH R35** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $708,000

## Abstract

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 wher...

## Key facts

- **NIH application ID:** 10753445
- **Project number:** 5R35GM144046-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Christine Mayr
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $708,000
- **Award type:** 5
- **Project period:** 2022-02-14 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10753445

## Citation

> US National Institutes of Health, RePORTER application 10753445, Regulation of protein multi-functionality by 3 UTRs (5R35GM144046-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10753445. Licensed CC0.

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