# Translational regulation during  cigarette smoking-induced reprogramming of the tRNA epitranscriptome, in vitro and in a mouse smoking model

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT ALBANY · 2024 · $377,990

## Abstract

1. PROJECT SUMMARY
Cigarette smoking causes cardiovascular disease, chronic obstructive pulmonary disease (COPD), and lung
cancer. The etiology of diseases caused by exposure to environmental tobacco smoke (ETS) is confounded by
the complexity of ETS as a mixture of >4000 chemicals, including direct-acting and metabolically-activated
toxicants. While all organisms respond to environmental exposures by regulating gene expression, we know little
about the translational mechanisms linking toxicant exposure to cell survival and disease. Here we seek to
understand the role of the dozens of modified ribonucleosides in tRNA – the tRNA epitranscriptome – in
regulating the cell response to ETS exposure. Using a unique computational and analytical platform, we have
shown that (1) toxicant exposures cause signature changes in the epitranscriptome of yeast and mammalian
cells, and (2) that toxicant-induced reprogramming of the tRNA epitranscriptome regulates protein levels by
promoting the selective translation of codon-biased mRNAs from families of stress-response genes in yeast. Our
studies in bacteria, yeast and mammalian cells1-7 also show that deficiencies in key epitranscriptomic writer
enzymes sensitize cells to killing by specific toxicants due to corrupted translation of stress response proteins.
We hypothesize that exposure to the complex mixture of ETS will reprogram the tRNA epitranscriptome
to reflect the predominant chemical stressors in ETS and that the altered RNA modifications will regulate
cell behavior by selective translation of codon-biased stress response mRNAs. In support of this, we have
observed agent-specific epitranscriptome reprogramming in the liver from rats exposed to drugs and toxicants
(e.g., arsenic; NTP DrugMatrix), and alkylation- and oxidation-specific signature tRNA modification changes in
yeast and human cells. Our epitranscriptomic writer-deficient (Alkbh8-null) mice showed that tRNA modification
systems required for translating oxidant-detoxifying selenoproteins are vital to surviving exposure to
naphthalene, a P450-activated, oxidant-generating, polycyclic aromatic hydrocarbon (PAH) in ETS. In three aims
ranging from in vitro studies in cultured mouse cells to a mouse ETS exposure model, we test the idea that the
epitranscriptome and translational regulation play an important role in the cell response to ETS.
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## Key facts

- **NIH application ID:** 10823293
- **Project number:** 5R01ES031529-05
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT ALBANY
- **Principal Investigator:** Thomas J Begley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $377,990
- **Award type:** 5
- **Project period:** 2020-06-09 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823293

## Citation

> US National Institutes of Health, RePORTER application 10823293, Translational regulation during  cigarette smoking-induced reprogramming of the tRNA epitranscriptome, in vitro and in a mouse smoking model (5R01ES031529-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10823293. Licensed CC0.

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