The impact of tRNA modifications on translation in cancer: identifying novel therapeutic avenues

Añazco-Guenkova, Ana M; Miguel-López, Borja; Monteagudo-García, Óscar; García-Vílchez, Raquel; Blanco, Sandra

doi:10.1093/narcan/zcae012

Cited by 6 publications

References 196 publications

(319 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

Queuosine tRNA Modification: Connecting the Microbiome to the Translatome

Rashad

2024

BioEssays

View full text Add to dashboard Cite

Transfer RNA (tRNA) modifications play an important role in regulating mRNA translation at the codon level. tRNA modifications can influence codon selection and optimality, thus shifting translation toward specific sets of mRNAs in a dynamic manner. Queuosine (Q) is a tRNA modification occurring at the wobble position. In eukaryotes, queuosine is synthesized by the tRNA‐guanine trans‐glycosylase (TGT) complex, which incorporates the nucleobase queuine (or Qbase) into guanine of the GUN anticodons. Queuine is sourced from gut bacteria and dietary intake. Q was recently shown to be critical for cellular responses to oxidative and mitochondrial stresses, as well as its potential role in neurodegenerative diseases and brain health. These unique features of Q provide an interesting insight into the regulation of mRNA translation by gut bacteria, and the potential health implications. In this review, Q biology is examined in the light of recent literature and nearly 4 decades of research. Q's role in neuropsychiatric diseases and cancer is highlighted and discussed. Given the recent interest in Q, and the new findings, more research is needed to fully comprehend its biological function and disease relevance, especially in neurobiology.

show abstract

Queuosine tRNA Modification: Connecting the Microbiome to the Translatome

Rashad

2024

BioEssays

View full text Add to dashboard Cite

show abstract

Chemotherapeutic agents and leucine deprivation induce codon-biased aberrant protein production in cancer

Kochavi,

Nagel,

Körner

et al. 2024

Nucleic Acids Research

View full text Add to dashboard Cite

Messenger RNA (mRNA) translation is a tightly controlled process frequently deregulated in cancer. Key to this deregulation are transfer RNAs (tRNAs), whose expression, processing and post-transcriptional modifications are often altered in cancer to support cellular transformation. In conditions of limiting levels of amino acids, this deregulated control of protein synthesis leads to aberrant protein production in the form of ribosomal frameshifting or misincorporation of non-cognate amino acids. Here, we studied leucine, an essential amino acid coded by six different codons. Surprisingly, we found that leucine deprivation leads to ribosomal stalling and aberrant protein production in various cancer cell types, predominantly at one codon, UUA. Similar effects were observed after treatment with chemotherapeutic agents, implying a shared mechanism controlling the downstream effects on mRNA translation. In both conditions, a limitation in the availability of tRNALeu(UAA) for protein production was shown to be the cause for this dominant effect on UUA codons. The induced aberrant proteins can be processed and immune-presented as neoepitopes and can direct T-cell killing. Altogether, we uncovered a novel mode of interplay between DNA damage, regulation of tRNA availability for mRNA translation and aberrant protein production in cancer that could be exploited for anti-cancer therapy.

show abstract

Closing in on human methylation—the versatile family of seven-β-strand (METTL) methyltransferases

Falnes

2024

Nucleic Acids Research

View full text Add to dashboard Cite

Methylation is a common biochemical reaction, and a number of methyltransferase (MTase) enzymes mediate the various methylation events occurring in living cells. Almost all MTases use the methyl donor S-adenosylmethionine (AdoMet), and, in humans, the largest group of AdoMet-dependent MTases are the so-called seven-β-strand (7BS) MTases. Collectively, the 7BS MTases target a wide range of biomolecules, i.e. nucleic acids and proteins, as well as several small metabolites and signaling molecules. They play essential roles in key processes such as gene regulation, protein synthesis and metabolism, as well as neurotransmitter synthesis and clearance. A decade ago, roughly half of the human 7BS MTases had been characterized experimentally, whereas the remaining ones merely represented hypothetical enzymes predicted from bioinformatics analysis, many of which were denoted METTLs (METhylTransferase-Like). Since then, considerable progress has been made, and the function of > 80% of the human 7BS MTases has been uncovered. In this review, I provide an overview of the (estimated) 120 human 7BS MTases, grouping them according to substrate specificities and sequence similarity. I also elaborate on the challenges faced when studying these enzymes and describe recent major advances in the field.

show abstract

The impact of tRNA modifications on translation in cancer: identifying novel therapeutic avenues

Cited by 6 publications

References 196 publications

Queuosine tRNA Modification: Connecting the Microbiome to the Translatome

Queuosine tRNA Modification: Connecting the Microbiome to the Translatome

Chemotherapeutic agents and leucine deprivation induce codon-biased aberrant protein production in cancer

Closing in on human methylation—the versatile family of seven-β-strand (METTL) methyltransferases

Contact Info

Product

Resources

About