Epitranscriptomic Reprogramming Is Required to Prevent Stress and Damage from Acetaminophen

Authors

Sara Evke, University at Albany, State University of New York
Qishan Li, University at Albany, State University of New York
Juan Andres Melendez, University at Albany, State University of New York
Thomas John Begley, University at Albany, State University of New York

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Document Type

Article

Publication Date

2-25-2022

DOI

https://doi.org/10.3390/genes13030421

Abstract

Epitranscriptomic marks, in the form of enzyme catalyzed RNA modifications, play important gene regulatory roles in response to environmental and physiological conditions. However, little is known with respect to how acute toxic doses of pharmaceuticals influence the epitranscriptome. Here we define how acetaminophen (APAP) induces epitranscriptomic reprogramming and how the writer Alkylation Repair Homolog 8 (Alkbh8) plays a key gene regulatory role in the response. Alkbh8 modifies tRNA selenocysteine (tRNA^Sec) to translationally regulate the production of glutathione peroxidases (Gpx’s) and other selenoproteins, with Gpx enzymes known to play protective roles during APAP toxicity. We demonstrate that APAP increases toxicity and markers of damage, and decreases selenoprotein levels in Alkbh8 deficient mouse livers, when compared to wildtype. APAP also promotes large scale reprogramming of many RNA marks comprising the liver tRNA epitranscriptome including: 5-methoxycarbonylmethyluridine (mcm⁵U), isopentenyladenosine (i⁶A), pseudouridine (Ψ), and 1-methyladenosine (m¹A) modifications linked to tRNA^Sec and many other tRNA’s. Alkbh8 deficiency also leads to wide-spread epitranscriptomic dysregulation in response to APAP, demonstrating that a single writer defect can promote downstream changes to a large spectrum of RNA modifications. Our study highlights the importance of RNA modifications and translational responses to APAP, identifies writers as key modulators of stress responses in vivo and supports the idea that the epitranscriptome may play important roles in responses to pharmaceuticals.

Comments

This is the Publisher’s PDF of the following article made available by Genes: Evke, S.; Lin, Q.; Melendez, J.A.; Begley, T.J. Epitranscriptomic Reprogramming Is Required to Prevent Stress and Damage from Acetaminophen. Genes 2022, 13, 421. https://doi.org/10.3390/genes13030421

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Evke, Sara; Li, Qishan; Melendez, Juan Andres; and Begley, Thomas John, "Epitranscriptomic Reprogramming Is Required to Prevent Stress and Damage from Acetaminophen" (2022). Biological Sciences Faculty Scholarship. 32.
https://scholarsarchive.library.albany.edu/biology_fac_scholar/32