# Coordination of RNA cleavage with end modification and processing

> **NIH NIH R35** · UNIVERSITY OF COLORADO DENVER · 2020 · $376,859

## Abstract

Abstract
Programmed or unintentional RNA cleavage leads to "dirty" RNA 5´ and 3´ ends
that are remodeled by RNA end modification enzymes. The products of RNA end
modification are substrates for RNA processing activities that catalyze RNA
repair, decay or stabilization. Because some processing enzymes recognize
different modified termini, RNA end modification enzymes could promote some
processing steps while inhibiting others. Conversely, RNA processing enzymes
that catalyze different reactions might recognize – and compete for – substrates
with the same end modification to control the outcome of RNA cleavage. These
different scenarios could potentially be used to regulate the outcome of RNA
cleavage, but we know very little about the roles of RNA end modification during
RNA processing. We discovered that RNA end modification by the RNA 5´-
kinase activity of the yeast tRNA ligase Trl1 is important to regulate the unfolded
protein response by phosphorylating RNA intermediates during unintentional
UPR activation to facilitate their turnover by 5´→3´ decay, and that Trl1 RNA 5´-
kinase activity mediates the turnover of mRNA fragments created by co-
translational “no-go” mRNA decay. The human RNA 5´-kinase enzyme Clp1 has
an important role in neuronal metabolism and differentiation, but we do not know
the substrates of Clp1 and so it is not clear how dysfunction in RNA 5´-kinase
activity leads to disease. Our discovery that Trl1 5´-kinase activity mediates the
decay of mRNA cleavage fragments also begs the question of whether the Trl1
ligase can also repair RNAs, but only a few examples of RNA repair are known.
To address these issues, we will focus on the following questions: 1. What are
the substrates of the human Clp1 RNA 5´-kinase?; 2. How do RNA end
modification and processing regulate the unfolded protein response?; 3. How are
the products of no-go mRNA decay created, and what are its physiological
substrates?; 4. Is RNA repair restricted to specific substrates, or does it act on
other damaged RNAs? The outcomes of these studies will be an improved
understanding of how RNA end modification is used after RNA cleavage to
mediate RNA processing, and these insights may inform our understanding of
how dysfunction in RNA end modification underlies human disease.

## Key facts

- **NIH application ID:** 9928940
- **Project number:** 5R35GM119550-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Jay R Hesselberth
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,859
- **Award type:** 5
- **Project period:** 2016-08-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928940

## Citation

> US National Institutes of Health, RePORTER application 9928940, Coordination of RNA cleavage with end modification and processing (5R35GM119550-05). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9928940. Licensed CC0.

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