ALKBH8
Alkylated DNA repair protein alkB homolog 8 (Probable alpha-ketoglutarate-dependent dioxygenase ABH8) (S-adenosyl-L-methionine-dependent tRNA methyltransferase ABH8) (tRNA (carboxymethyluridine(34)-5-O)-methyltransferase ABH8) (EC 2.1.1.229) [ABH8]
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Critically important to the maintenance of the glutathione (GSH) redox cycle are the activities of many selenocysteine-containing GSH metabolizing enzymes whose translation is controlled by the epitranscriptomic writer alkylation repair homolog 8 (ALKBH8). ALKBH8 is a tRNA methyltransferase that methylates the wobble uridine of specific tRNAs to regulate the synthesis of selenoproteins. Here we demonstrate that a deficiency in the writer ALKBH8 (Alkbh8 ), alters selenoprotein levels and engages senescence, regulates stress response genes and promotes mitochondrial reprogramming. Alkbh8 mouse embryonic fibroblasts (MEFs) increase many hallmarks of senescence, including senescence associated β-galactosidase, heterocromatic foci, the cyclin dependent kinase inhibitor p16 , markers of mitochondrial dynamics as well as the senescence associated secretory phenotype (SASP). Alkbh8 cells also acquire a stress resistance phenotype that is accompanied by an increase in a number redox-modifying transcripts. In addition, Alkbh8 MEFs undergo a metabolic shift that is highlighted by a striking increase in the level of uncoupling protein 2 (UCP2) which enhances oxygen consumption and promotes a reliance on glycolytic metabolism. Finally, we have shown that the Alkbh8 deficiency can be exploited and corresponding MEFs are killed by glycolytic inhibition. Our work demonstrates that defects in an epitransciptomic writer promote senescence and mitochondrial reprogramming and unveils a novel adaptive mechanism for coping with defects in selenocysteine utilization.
MeSH Terms
- AlkB Homolog 8, tRNA Methyltransferase
- Animals
- Cells, Cultured
- Cellular Senescence
- Epigenesis, Genetic
- Gene Deletion
- Gene Expression Profiling
- Humans
- Mice
- Mitochondria
- Oxygen Consumption
- Selenocysteine
- Uncoupling Protein 2
Keywords
- Epitranscriptome
- Mitochondria
- Selenium
- Senescence
- Uncoupling protein
ALKB-8 is a 2-oxoglutarate-dependent dioxygenase homologous to bacterial AlkB, which oxidatively demethylates DNA substrates. The mammalian AlkB family contains AlkB homologues denominated ALKBH1 to 8 and FTO. The C. elegans genome includes five AlkB-related genes, homologues of ALKBH1, 4, 6, 7, and 8, but lacks homologues of ALKBH2, 3, and 5 and FTO. ALKBH8 orthologues differ from other AlkB family members by possessing an additional methyltransferase module and an RNA binding N-terminal module. The ALKBH8 methyltransferase domain generates the wobble nucleoside 5-methoxycarbonylmethyluridine from its precursor 5-carboxymethyluridine and its (R)- and (S)-5-methoxycarbonylhydroxymethyluridine hydroxylated forms in tRNA Arg/UCG and tRNA Gly/UCC. The ALKBH8/ALKB-8 methyltransferase domain is highly similar to yeast TRM9, which selectively modulates translation of mRNAs enriched with AGA and GAA codons under both normal and stress conditions. In this report, we studied the role of alkb-8 in C. elegans. We show that downregulation of alkb-8 increases detection of lysosome-related organelles visualized by Nile red in vivo. Reversely, forced expression of alkb-8 strongly decreases the detection of this compartment. In addition, overexpression of alkb-8 applied in a pulse during the L1 larval stage increases the C. elegans lifespan.
MeSH Terms
- Aging
- AlkB Enzymes
- Animals
- Animals, Genetically Modified
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
- Dioxygenases
- Down-Regulation
- Embryo, Nonmammalian
- Gene Expression Regulation, Developmental
- Green Fluorescent Proteins
- Ketoglutaric Acids
- Larva
- Longevity
- Lysosomes
- Methyltransferases
- Operon
- Promoter Regions, Genetic
- RNA Interference
- S-Adenosylmethionine