# Non-canonical mechanisms of translation initiation and regulation

> **NIH NIH R35** · OHIO STATE UNIVERSITY · 2022 · $381,998

## Abstract

ABSTRACT
My previous work showed specific mutations in mRNAs activate initiation at non-canonical start codons (e.g.,
GUG, ACG) resulting in expression of neurotoxic proteins that cause multiple human disorders. However, non-
canonical translation is not restricted to atypical start codons or necessarily connected to pathology; cells rely
on alternative mechanisms to respond to specific states to translate mRNAs with spatiotemporal precision. Our
basic understanding of non-canonical translation is incomplete, and the long-term goal of this research
program is to understand how and why non-canonical translation occurs in cells. We will fill gaps in our
understanding of non-canonical initiation by addressing two fundamental questions. What mechanisms enable
alternative initiation factors to support translation? Which aminoacyl tRNAs other than Met-tRNAiMet are used
for initiation? Our previous and current work has also discovered unconventional translational regulatory
mechanisms that use ribosome queuing and non-canonical RNA-binding domains (ncRBDs). We will establish
how unconventional regulatory mechanisms such as ribosome queuing are used as cellular sensors of
elongation to drive apoptosis, and how proteins with ncRBDs regulate translation. My research program will
shed new light on how the translation machinery is used to create a diverse repertoire of initiation and
regulatory mechanisms. In doing so, we will expand our understanding of the coding potential of the genome
and how alterations in protein synthesis lead to human disease.

## Key facts

- **NIH application ID:** 10498134
- **Project number:** 1R35GM146924-01
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Michael G Kearse
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $381,998
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10498134

## Citation

> US National Institutes of Health, RePORTER application 10498134, Non-canonical mechanisms of translation initiation and regulation (1R35GM146924-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10498134. Licensed CC0.

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