Selenoproteins and the senescence-associated epitranscriptome

Abstract

Selenium is a naturally found trace element, which provides multiple benefits including antioxidant, anticancer, and antiaging, as well as boosting immunity. One unique feature of selenium is its incorporation as selenocysteine, a rare 21st amino acid, into selenoproteins. Twenty-five human selenoproteins have been discovered, and a majority of these serve as crucial antioxidant enzymes for redox homeostasis. Unlike other amino acids, incorporation of selenocysteine requires a distinctive UGA stop codon recoding mechanism. Although many studies correlating selenium, selenoproteins, aging, and senescence have been performed, it has not yet been explored if the upstream events regulating selenoprotein synthesis play a role in senescence-associated pathologies. The epitranscriptomic writer alkylation repair homolog 8 (ALKBH8) is critical for selenoprotein production, and its deficiency can significantly decrease levels of selenoproteins that are essential for reactive oxygen species (ROS) detoxification, and increase oxidative stress, one of the major drivers of cellular senescence. Here, we review the potential role of epitranscriptomic marks that govern selenocysteine utilization in regulating the senescence program.

Behavioral and Cognitive Performance Following Exposure to Second-Hand Smoke (SHS) from Tobacco Products Associated with Oxidative-Stress-Induced DNA Damage and Repair and Disruption of the Gut Microbiome

“…We also assessed the effects of SHS on the percentage of p21-labeled cells, an early cellular marker of senescence [ 41 ] that is upregulated in bronchial cells after exposure to cigarette smoke [ 42 ]. Nuclear staining of p21-labeled cells was more prominent in larger cells of the prefrontal cortex ( Figure 5 A) and CA1 hippocampal neurons ( Figure 5 B) of SHS-exposed mice than in sham-exposed mice.…”

Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer

“…From these analyses, we identified the tRNA-methyltransferase AlkBH8 as a potential novel therapeutic target in CRC, as high AlkBH8 expression correlates with decreased overall survival in CRC patients (Figure 5A-B). AlkBH8 has been extensively reported to regulate the selenoproteome via methylation of tRNA-selenocysteine, with AlkBH8 knockdown and knockout models demonstrating a decreased ability to translate selenoproteins [54][55][56][57][58][59][60][61] . We observed that AlkBH8 expression is significantly increased in tumor tissue as compared to normal controls (Figure 5C), and that patients with early-onset CRC have increased expression of AlkBH8 as compared to all other age groups (Figure 5D).…”

tRNA modification enzyme-dependent redox homeostasis regulates synapse formation and memory

“…Loss of ALKBH8 and its associated methylation disrupts DNA repair and oxidative stress responses as well as cellular senescence and mitochondrial activity in mammalian cells (47)(48)(49)(50)(51)(52). ALKBH8 regulates oxidative stress via regulation of selenoprotein synthesis, which relies on methylation of tRNA-selenocysteine (tRNA Sec ) for recoding UGA stop codons.…”