Date of Award

Spring 5-2021

Document Type

Honors Thesis

Degree Name

Bachelor of Science

Department

Biology

Advisor/Committee Chair

Richard Cunningham

Major

Biology

Committee Member

Thomas Begley

Abstract

The Central Dogma of Molecular Biology states that DNA goes to RNA to proteins through the process of transcription and translation. tRNAs have numerous post transcriptional modifications that promote anticodon-codon interactionns and protein synthesis. The spectrum of RNA modifications is collectively known as the epitranscriptome, and modification defects can disrupt cytoplasmic and mitochondrial protein synthesis and are linked to human disease. RNA methyltransferases catalyzes the reaction between a methyl group to a nucleoside residue. Alkylation repair homolog 8 (ALKBH8) completes the formation of wobble uridine (U) modifications through the addition of a methyl group to promote the specialized translation of selenoproteins, which assist with the detoxification of reactive oxygen species (ROS). Deficiencies in Alkbh8 (Alkbh8def) in C57BL/6J mice are known to decrease wobble U modifications, disrupt glutathione biology, promote sensitivity to ROS, disrupt stress responses, and are linked to cancer and intellectual disability. In my project, I used computational approaches and literature review to determine if Alkbh8 and other RNA modification enzymes can be linked to diseases of the brain and pharmaceutical responses. It has been reported that Alkbh8 defects are linked to intellectual disability. The pharmaceutical exposure that I specifically analyzed was acetaminophen (APAP), an over-the-counter medicine that decreases pain and fever in humans. The excess use of acetaminophen leads to death, emergency hospital visits, and even acute liver failure. After thorough analysis, p53 was up-regulated by a 5-fold change in WT livers treated with APAP vs. WT saline, consistent with stress induced gene regulation. Nrep was down-regulated by a 5-fold change in WT livers treated with APAP vs. WT saline. We also found that Sec24a was up-regulated in Alkbh8def treated livers related to WT treated, which is linked to APAP hepatotoxicity. Also in Alkbh8def treated livers related to WT treated, we saw an upregulation with antigen processing and immunodeficiences that suggests antibody production decreased when mice received high dosages o fAPAP. Transcriptional analysis of the APAP reponse has identified that APAP can induce stress and some transcripts have altered regulation in Alkbh8def treated livers.

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