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

Madhwani, Kimberly R.; Sayied, Shanzeh; Ogata, Carlson H.; Hogan, Caley A.; Lentini, Jenna M.; Mallik, Moushami; Dumouchel, Jennifer L.; Storkebaum, Erik; Fu, Dragony; O’Connor-Giles, Kate M.

doi:10.1101/2023.11.14.566895

Cited by 3 publications

(1 citation statement)

References 137 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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).…”

Section: Investigating the Selenoproteome As A Therapeutic Target In ...mentioning

confidence: 99%

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

DeAngelo,

Dziechciarz,

Solanki

et al. 2024

Preprint

View full text Add to dashboard Cite

Ferroptosis is an iron-dependent, non-apoptotic form of cell death resulting from the accumulation of lipid peroxides. Colorectal cancer (CRC) accumulates high levels of intracellular iron and reactive oxygen species (ROS), thereby sensitizing cells to ferroptosis. The selenoprotein glutathione peroxidase (GPx4) is a key enzyme in the detoxification of lipid peroxides and can be inhibited by the compound (S)-RSL3 ([1S,3R]-RSL3). However, the stereoisomer (R)-RSL3 ([1R,3R]-RSL3), which does not inhibit GPx4, exhibits equipotent activity to (S)-RSL3 across a panel of CRC cell lines. Utilizing CRC cell lines with an inducible knockdown of GPx4, we demonstrate that (S)-RSL3 sensitivity does not align with GPx4 dependency. Subsequently, a biotinylated (S)-RSL3 was then synthesized to perform affinity purification-mass spectrometry (AP-MS), revealing that (S)-RSL3 acts as a pan-inhibitor of the selenoproteome, targeting both the glutathione and thioredoxin peroxidase systems as well as multiple additional selenoproteins. To investigate the therapeutic potential of broadly disrupting the selenoproteome as a therapeutic strategy in CRC, we employed further chemical and genetic approaches to disrupt selenoprotein function. The findings demonstrate that the selenoprotein inhibitor Auranofin can induce ferroptosis and/or oxidative cell death both in-vitro and in-vivo. Consistent with this data we observe that AlkBH8, a tRNA-selenocysteine methyltransferase required for the translational incorporation of selenocysteine, is essential for CRC growth. In summary, our research elucidates the complex mechanisms underlying ferroptosis in CRC and reveals that modulation of the selenoproteome provides multiple new therapeutic targets and opportunities in CRC.

show abstract

Section: Investigating the Selenoproteome As A Therapeutic Target In ...mentioning

confidence: 99%

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

DeAngelo,

Dziechciarz,

Solanki

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

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

Madhwani,

Sayied,

Ogata

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Post-transcriptional modification of RNA regulates gene expression at multiple levels. ALKBH8 is a tRNA-modifying enzyme that methylates wobble uridines in a subset of tRNAs to modulate translation. Through methylation of tRNA-selenocysteine, ALKBH8 promotes selenoprotein synthesis and regulates redox homeostasis. Pathogenic variants in ALKBH8 have been linked to intellectual disability disorders in the human population, but the role of ALKBH8 in the nervous system is unknown. Through in vivo studies in Drosophila , we show that ALKBH8 controls oxidative stress in the brain to restrain synaptic growth and support learning and memory. ALKBH8 null animals lack wobble uridine methylation and exhibit reduced protein synthesis in the nervous system, including a specific decrease in selenoprotein levels. Either loss of ALKBH8 or independent disruption of selenoprotein synthesis results in ectopic synapse formation. Genetic expression of antioxidant enzymes fully suppresses synaptic overgrowth in ALKBH8 null animals, confirming oxidative stress as the underlying cause of dysregulation. ALKBH8 null animals also exhibit associative memory impairments that are reversed by pharmacological antioxidant treatment. Together, these findings demonstrate the critical role of tRNA wobble uridine modification in redox homeostasis in the developing nervous system and reveal antioxidants as a potential therapy for ALKBH8-associated intellectual disability.

show abstract

Dealkylation of Macromolecules by Eukaryotic α-Ketoglutarate-Dependent Dioxygenases from the AlkB-like Family

Davletgildeeva,

Kuznetsov

2024

CIMB

View full text Add to dashboard Cite

Alkylating modifications induced by either exogenous chemical agents or endogenous metabolites are some of the main types of damage to DNA, RNA, and proteins in the cell. Although research in recent decades has been almost entirely devoted to the repair of alkyl and in particular methyl DNA damage, more and more data lately suggest that the methylation of RNA bases plays an equally important role in normal functioning and in the development of diseases. Among the most prominent participants in the repair of methylation-induced DNA and RNA damage are human homologs of Escherichia coli AlkB, nonheme Fe(II)/α-ketoglutarate-dependent dioxygenases ABH1–8, and FTO. Moreover, some of these enzymes have been found to act on several protein targets. In this review, we present up-to-date data on specific features of protein structure, substrate specificity, known roles in the organism, and consequences of disfunction of each of the nine human homologs of AlkB. Special attention is given to reports about the effects of natural single-nucleotide polymorphisms on the activity of these enzymes and to potential consequences for carriers of such natural variants.

show abstract

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

Cited by 3 publications

References 137 publications

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

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

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

Dealkylation of Macromolecules by Eukaryotic α-Ketoglutarate-Dependent Dioxygenases from the AlkB-like Family

Contact Info

Product

Resources

About