Growing prospects of RNA therapeutics: A case of METTL5 and 18S rRNA m6A modification

The central dogma of molecular biology and genetics considers RNA molecules as mere messengers for decoding genetic information in living cells. 1 Li G.-W. Xie X.S. Central dogma at the single-molecule level in living cells. Nature. 2011; 475: 308-315 Crossref PubMed Scopus (330) Google Scholar However, current knowledge demonstrates the significant influence of RNA biology on genetic, physiological, and biochemical regulation at various stages of disease and development. 2 Barta A. Jantsch M.F. RNA in disease and development. RNA Biol. 2017; 14: 457-459 Crossref PubMed Scopus (8) Google Scholar RNA molecules play a crucial role in shaping intricate cellular systems, specifically in the spliceosome and ribosome assembly. Further, diverse RNA modifications with yet to be fully assigned biological functions underscore the overarching role of ribosomal RNA (rRNA) in framing regulatory networks. Developmental and tissue-specific modification of RNAs, including messenger RNA (mRNA), transfer RNA (tRNA), and rRNA—significantly impacts regulatory processes, facilitating the precise control of several gene-specific pathways. Previous investigations into abnormalities in RNA processing and modifications have resulted in rapid progress in understanding some critical human diseases. 3 Nussbacher J.K. Tabet R. Yeo G.W. Lagier-Tourenne C. Disruption of RNA Metabolism in Neurological Diseases and Emerging Therapeutic Interventions. Neuron. 2019; 102: 294-320 Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar ,4 Christofi T. Zaravinos A. RNA editing in the forefront of epitranscriptomics and human health. J. Transl. Med. 2019; 17: 319 Crossref PubMed Scopus (80) Google Scholar These modifications have helped significantly elaborate the base selection from four canonical nucleotides (A-U(T)-G-C) to additional layers of m6A, m5C, m1A, m7G, ac4C, Ψ, etc. Moreover, research on the possibilities of cellular abnormalities in human diseases has exploded since the discovery of RNA modifications influencing dendritic cells and Toll-like receptor (TLR)-expressing cells. 5 Karikó K. Buckstein M. Ni H. Weissman D. Suppression of RNA Recognition by Toll-like Receptors: The Impact of Nucleoside Modification and the Evolutionary Origin of RNA. Immunity. 2005; 23: 165-175 Abstract Full Text Full Text PDF PubMed Scopus (1542) Google Scholar Specifically, defects in RNA processing have been identified as significant contributors to human disease development, 3 Nussbacher J.K. Tabet R. Yeo G.W. Lagier-Tourenne C. Disruption of RNA Metabolism in Neurological Diseases and Emerging Therapeutic Interventions. Neuron. 2019; 102: 294-320 Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar which is explored in a recent article in Molecular Therapy by Dai and colleagues. 6 Dai Z. Zhu W. Hou Y. Zhang X. Ren X. Lei K. Liao J. Liu H. Chen Z. Peng S. et al. METTL5-mediated 18S rRNA m6A modification promotes oncogenic mRNA translation and intrahepatic cholangiocarcinoma progression. Mol. Ther. 2023; 31: 3225-3242 Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar