Compartment-specific m7G RNA modification in cancer: mechanisms, tumor adaptation, and therapeutic vulnerabilities
Abstract
N7-methylguanosine (m7G) is distributed across several RNA classes and regulates distinct stages of gene expression. The best-characterized form is the 5′cap of messenger RNA, although m7G also occurs in transfer RNA, ribosomal RNA, internal messenger RNA, circular RNA, and transfer RNA-derived small RNAs. Cancer-associated m7G dysregulation therefore cannot be ascribed to a single enzyme or molecular outcome. The strongest causal evidence concerns the METTL1-WDR4 complex, which modifies transfer RNA and reshapes codon-biased translation, promoting proliferation, metastasis, metabolic adaptation, stress tolerance, and treatment resistance. Studies of internal messenger RNA m7G report reader-dependent effects on stability, decay, translation, and stress-granule partitioning. Cap biochemistry is established, whereas catalytic cancer mechanisms involving ribosomal RNA remain less resolved. In preclinical models, these pathways connect tumor-cell adaptation with stromal communication, immune evasion, and treatment response. The biological effects of m7G vary with the modified RNA and the proteins favored by translation; tumor-restrictive activity emerges when altered tRNA modification increases the production of cell-cycle inhibitory proteins. This review organizes established and emerging mechanisms by RNA compartment and examines the substrate-dependent balance between tumor promotion, tumor restriction, and treatment sensitivity. It also evaluates biomarker strategies, emerging pharmacological and RNA-directed interventions, and the methodological standards needed to distinguish direct m7G-dependent effects from regulator expression correlations. A site-resolved, substrate-specific understanding of m7G may reveal translational dependencies that are actionable without disrupting essential RNA metabolism in normal tissues.
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BibTeX
@article{tian2026compartmentspecific,
title = {{Compartment-specific m7G RNA modification in cancer: mechanisms, tumor adaptation, and therapeutic vulnerabilities}},
author = {Xiaoxiao Tian and Di Huang and Chaonan Guan},
journal = {Frontiers in Molecular Biosciences},
year = {2026},
month = oct,
doi = {10.3389/fmolb.2026.1951991},
url = {https://www.frontiersin.org/articles/10.3389/fmolb.2026.1951991},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Compartment-specific m7G RNA modification in cancer: mechanisms, tumor adaptation, and therapeutic vulnerabilities
AU - Xiaoxiao Tian
AU - Di Huang
AU - Chaonan Guan
PY - 2026
DA - 2026/10/29
JO - Frontiers in Molecular Biosciences
DO - 10.3389/fmolb.2026.1951991
UR - https://www.frontiersin.org/articles/10.3389/fmolb.2026.1951991
AB - N7-methylguanosine (m7G) is distributed across several RNA classes and regulates distinct stages of gene expression. The best-characterized form is the 5′cap of messenger RNA, although m7G also occurs in transfer RNA, ribosomal RNA, internal messenger RNA, circular RNA, and transfer RNA-derived small RNAs. Cancer-associated m7G dysregulation therefore cannot be ascribed to a single enzyme or molecular outcome. The strongest causal evidence concerns the METTL1-WDR4 complex, which modifies transfer RNA and reshapes codon-biased translation, promoting proliferation, metastasis, metabolic adaptation, stress tolerance, and treatment resistance. Studies of internal messenger RNA m7G report reader-dependent effects on stability, decay, translation, and stress-granule partitioning. Cap biochemistry is established, whereas catalytic cancer mechanisms involving ribosomal RNA remain less resolved. In preclinical models, these pathways connect tumor-cell adaptation with stromal communication, immune evasion, and treatment response. The biological effects of m7G vary with the modified RNA and the proteins favored by translation; tumor-restrictive activity emerges when altered tRNA modification increases the production of cell-cycle inhibitory proteins. This review organizes established and emerging mechanisms by RNA compartment and examines the substrate-dependent balance between tumor promotion, tumor restriction, and treatment sensitivity. It also evaluates biomarker strategies, emerging pharmacological and RNA-directed interventions, and the methodological standards needed to distinguish direct m7G-dependent effects from regulator expression correlations. A site-resolved, substrate-specific understanding of m7G may reveal translational dependencies that are actionable without disrupting essential RNA metabolism in normal tissues.
SN - 2296-889X
ER -