The impact of tRNA modifications on translation in cancer - identifying novel therapeutic avenues - Ana M. Añazco-Guenkova and coauthors

Sep 21, 2026

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Recent advancements highlight how RNA modifications reshape post-transcriptional regulation and the broader gene-expression landscape. This review focuses on tRNA modifications as key fine-tuners of protein-synthesis fidelity while also shaping gene-expression and translation profiles. By examining cytosolic and mitochondrial tRNA modifications, it links their dysregulation to cancer biology, influencing proliferation, tumorigenesis, migration, metastasis, bioenergetics, and tumor-immune microenvironment modulation. Recurring altered modification patterns suggest roles as biomarkers and actionable therapeutic targets for precision medicine.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages19

Reading Time48 min

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Abstract

Introduction

Translational regulation in protein synthesis

The impact of tRNA modifications on translation in cancer: identifying novel therapeutic avenues Ana M. Añazco-Guenkova 1 ,2 ,†, Borja Miguel-López1 ,2 ,†, Óscar Monteagudo-García1 ,2 ,†, Raquel García-Vílchez 1 ,2 and Sandra Blanco 1 ,2 , * 1 Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) -University of Salamanca, 37007 Salamanca, Spain 2 Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, 37007 Salamanca, Spain * To whom correspondence should be addressed. Email: [sandra.blanco@usal.es](sandra.blanco@usal.es)[ ](sandra.blanco@usal.es)†The first three authors should be regarded as Joint First Authors. Abstract Recent advancements have illuminated the critical role of RNA modifications in post-transcriptional regulation, shaping the landscape of gene expression. This review explores how tRNA modifications emerge as critical players, fine-tuning functionalities that not only maintain the fidelity of protein synthesis but also dictate gene expression and translation profiles. Highlighting their dysregulation as a common denominator in various cancers, we systematically investigate the intersection of both cytosolic and mitochondrial tRNA modifications with cancer biology. These modifications impact key processes such as cell proliferation, tumorigenesis, migration, metastasis, bioenergetics and the modulation of the tumor immune microenvironment. The recurrence of altered tRNA modification patterns across different cancer types underscores their significance in cancer development, proposing them as potential biomarkers and as actionable targets to disrupt tumorigenic processes, offering new avenues for precision medicine in the battle against cancer. Graphical abstract tRF biogenesis Degradation Codon bias/aa recognition Homeostasis Cancer Overexpression Oncogenesis Introduction Protein synthesis is a highly preserved mechanism that involves the assembly of amino acids on ribosomes according to an messenger RNA (mRNA) template sequence. Translational control is crucial in modulating gene expression. Its significance extends to defining the proteome, ensuring homeostasis and governing cell proliferation, growth and development. Dysregulation of protein synthesis lies at the core of numerous diseases, underscoring the crucial need to understand the molecular foundations and intricate mechanisms of translational control (1) . Generally, protein synthesis is divided into three major steps: initiation, elongation and termination. The primary stage of regulation occurs during the recognition and decoding of the AUG start codon, managed by the methionyl-tRNA specialized for initiation (tRNAiMet ) . In eukaryotes, a scanning mechanism is employed, where the small (40S) ribosomal subunit, loaded with tRNAiMet in a 43S pre-initiation complex (PIC), together with the eukaryotic initiation factors (eIFs) eiF2-TC, eIF3, eIF1 and eIF5, attaches to the mRNA near the 5􀀂 end and scans the 5􀀂 -untranslated region (5􀀂UTR) to identify an AUG (or less frequently a near-cognate AUG) codon. The mRNA is activated for 43S binding by the formation of the translation initiation complex eIF4F (eIF4A, eIF4B, eIF4E and eIF4E), which recognizes the mRNA’s m7 G cap structure at the 5􀀂 end and interacts with poly(A) tail-binding protein (PABP) at the 3􀀂 end (2,3), forming the 48S ribosomal complex. Then, 60S ribosomes are recruited via eIF2-GTP activation, leaving the active 80S ribosomes to enter the extension phase (1). Then, protein elongation is produced by formation of a peptide bond of the aminoacyl-transfer RNAs complementary to the mRNA codon with the peptide attached to the ribosome P-site, followed by translocation of the ribosome. This process, promoted by distinct elongation factors and by the ribosome, is repeated until a termination codon enters the A-site, when termina

FAQs

How do tRNA modifications influence translation in cancer?

They act as critical regulators that fine-tune translation fidelity and also shape gene-expression and translation profiles. Their dysregulation is associated with multiple cancer-related processes described in the review.

What cellular functions are affected by altered tRNA modification patterns?

The document highlights effects on cell proliferation, tumorigenesis, migration, metastasis, bioenergetics, and modulation of the tumor immune microenvironment.

Why are tRNA modifications proposed as biomarkers or therapeutic targets?

Because altered tRNA modification patterns recur across different cancer types, they can serve as biomarkers and as actionable targets to disrupt tumorigenic processes, supporting new precision-medicine avenues.

Sep 21, 2026

Uploaded by Anda