# mRNA Template-free Protein Elongation: a New Paradigm for Quality Control at the Ribosome

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $321,800

## Abstract

Project Summary
This research effort seeks to increase fundamental knowledge about how cells handle failures in protein
synthesis and how these failures can lead to disease. Protein synthesis by the ribosome can abnormally halt
(“stall”) for numerous reasons, including faulty mRNA, insufficient availability of translation components, and
genetic errors. Handling these failures is critical, as abnormal responses to stalled protein synthesis have been
demonstrated to cause neurodegeneration. To cope with this burden, eukaryotic cells employ a process called
Ribosome-associated Quality Control (RQC) that detects stalled ribosomes and promotes degradation of the
protein that the ribosome was previously synthesizing (the “stalled nascent chain”). As part of RQC, we
discovered that the protein Rqc2 hijacks the ribosome to append Carboxy-terminal Alanine and Threonine
residues (“CAT tails”) to the stalled nascent chain. CAT tails benefit cells by marking stalled nascent chains for
degradation. Curiously, CAT tails can also harm cells by forming toxic aggregates that impair cellular viability.
How CAT tails possess these seemingly contradictory behaviors (beneficial vs. toxic) remains unclear. This
research program will address this knowledge gap by using biochemical, cell biological, and genomic
approaches to study: 1) how cells synthesize CAT tails , 2) how cells degrade CAT tails, and 3) how CAT tails
behave in metazoans. This study will elucidate a fundamental mechanism cells use to protect themselves from
failed protein synthesis and uncover the causes and consequences of its misregulation.

## Key facts

- **NIH application ID:** 10052220
- **Project number:** 2R01GM115968-06
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Onn Brandman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $321,800
- **Award type:** 2
- **Project period:** 2015-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10052220

## Citation

> US National Institutes of Health, RePORTER application 10052220, mRNA Template-free Protein Elongation: a New Paradigm for Quality Control at the Ribosome (2R01GM115968-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10052220. Licensed CC0.

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