All currently known mt-RNA modifications, their potential regulatory machinery, as well as their biological functions in tumorigenesis and metabolism are summarized.
Abstract
RNA modifications are essential in regulating gene expression at the post-transcriptional level. Recent studies, including our own, have highlighted that RNA modifications, such as N6-methyladenosine (m6A) and methyl-5-cytosine (m5C), play a crucial role in tumorigenesis, metabolism, and anti-tumor immunity. Targeting RNA modification machinery may represent a promising therapeutic strategy in cancer. Intriguingly, emerging evidence reveals numerous modifications in mitochondrial RNA (mt-RNA), expanding the concept of epitranscriptomics to mitochondria. The mammalian mitochondrion possesses its own genome, which encodes 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), and 13 proteins necessary for energy production via oxidative phosphorylation (OxPhos). The mitochondrial transcriptome is produced from large polycistronic transcripts, implying that mitochondrial gene expression is predominantly regulated post-transcriptionally. In this review, we summarize all currently known mt-RNA modifications, their potential regulatory machinery, as well as their biological functions in tumorigenesis and metabolism. Additionally, given that this field is still in its infancy, we discuss several critical knowledge gaps and propose future research directions to clarify the mechanistic and clinical significance in the study of mt-RNA modifications.
RNA-binding proteins (RBPs) are central regulators of post-transcriptional gene expression, recognizing RNAs through sequence, structure, and chemical modifications. Post-transcriptional RNA modifications, including m6A, m1A, m5C, m7G, and pseudouridine (Ψ), form the epitranscriptome, a dynamic regulatory layer that modulates RNA stability, localization, and translation. These modifications are interpreted by specialized “reader” RBPs that translate epitranscriptomic marks into functional outcomes. Dysregulation of RNA modifications or their associated reader RBPs has been increasingly linked to the development of cancers, neurological disorders, and other diseases, highlighting their potential for therapeutic manipulation. This review summarizes key RNA modifications and regulating RBPs with a specific emphasis on how dysregulation can lead to cancers. We further discuss current approaches for investigating and manipulating reader RBP–RNA interactions, highlighting how these methods enable new opportunities for therapeutic discovery.
G. Vega-Hernández, Amanda L. Garner· RSC Chemical Biology· 0 citations
This review integrates the molecular logic of splice-site selection with the cancer-specific mechanisms that perturb it, summarizes representative isoform switches across the hallmarks of cancer, evaluates emerging technologies and clinical biomarkers, and discusses the opportunities and constraints of translating splicing biology into precision oncology.
Transfer RNA-derived small RNAs (tsRNAs) represent an emerging class of non-coding RNAs involved in gene expression and cellular homeostasis. Growing evidence suggests that tsRNAs contribute to tumor initiation and progression, in part by reshaping the tumor microenvironment (TME). This review systematically summarizes the biogenesis and molecular mechanisms of tsRNAs and discusses how they regulate key TME-associated processes, including immune cell function, metabolic reprogramming, angiogenesis, and extracellular vesicle-mediated intercellular communication. We further examine their clinical relevance, focusing on circulating biomarkers, therapeutic targeting and delivery strategies, as well as current limitations for translation. In the tumor microenvironment, tRNA-derived small RNAs regulate multiple interconnected processes, including immunosuppression, metabolic reprogramming, angiogenesis, and extracellular vesicle-mediated cell-cell communication, thereby contributing to tumor progression. In the tumor microenvironment, tRNA-derived small RNAs regulate multiple interconnected processes, including immunosuppression, metabolic reprogramming, angiogenesis, and extracellular vesicle-mediated cell-cell communication, thereby contributing to tumor progression.
N6-methyladenosine (m6A) RNA methylation is the most prevalent internal modification in eukaryotic mRNA and precisely regulates gene expression by regulating the RNA life cycle. Lactate, a central glycolytic metabolite, can transduce cellular metabolic states into epigenetic signals through protein lactylation, an emerging post-translational modification. Because both modifications are highly responsive to cellular metabolic status, they have emerged as important regulators of the metabolic-epigenetic interface. Increasing evidence supports a bidirectional regulatory crosstalk between m6A modification and protein lactylation. Lactate accumulation can modulate the expression and activity of m6A-related regulatory enzymes through histone and non-histone lactylation; conversely, m6A modification can reshape glycolysis and lactate metabolism, thereby altering lactate availability and protein lactylation. This reciprocal regulation has been implicated in a broad spectrum of diseases, including cancer, metabolic disorders, cardiovascular diseases, and immune-inflammatory conditions. In this review, the molecular mechanisms of m6A modification and protein lactylation are systematically summarized, with particular emphasis on their modes of interaction and pathological relevance. Current limitations and future perspectives are also discussed, providing a conceptual framework for elucidating disease mechanisms and developing therapeutic strategies targeting this regulatory network.
Y. Gong, Yu Liu· Journal of Translational Med...· 0 citations
This review focuses on the interplay between immunity and epitranscriptomics and explores the direct and indirect effects of m6A modification on T cells and highlights the pivotal role of m6A regulation in T cell biology and its potential to optimize next-generation immunotherapies.
Yumna A. Butt, Nordin D. Zandhuis, I. Foskolou· Immuno· 0 citations
This review examines how different types of ncRNAs contribute to cancer initiation, progression, and treatment resistance, and assesses their potential as diagnostic markers, prognostic factors, and therapeutic targets.
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