Abstract
RNA modifications have recently emerged as a widespread and complex facet of gene expression regulation. Counting more than 170 distinct chemical modifications with far-reaching implications for RNA fate, they are collectively referred to as the epitranscriptome. These modifications can occur in all RNA species, including messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs). In mRNAs the deposition, removal, and recognition of chemical marks by writers, erasers and readers influence their structure, localization, stability, and translation. In turn, this modulates key molecular and cellular processes such as RNA metabolism, cell cycle, apoptosis, and others. Unsurprisingly, given their relevance for cellular and organismal functions, alterations of epitranscriptomic marks have been observed in a broad range of human diseases, including cancer, neurological and metabolic disorders. Here, we will review the major types of mRNA modifications and editing processes in conjunction with the enzymes involved in their metabolism and describe their impact on human diseases. We present the current knowledge in an updated catalog. We will also discuss the emerging evidence on the crosstalk of epitranscriptomic marks and what this interplay could imply for the dynamics of mRNA modifications. Understanding how this complex regulatory layer can affect the course of human pathologies will ultimately lead to its exploitation toward novel epitranscriptomic therapeutic strategies.
Highlights
RNA molecules can undergo more than 170 different chemical modifications (Boccaletto et al 2018)
A broad set of RNA-binding proteins (RBPs) determines the messenger RNAs (mRNAs) epitranscriptome: Modifications are induced by writers, and several can be reverted by erasers
We will give particular focus on the most abundant ones, namely RNA editing (A-to-I and C-to-U), N6-methyladenosine (m6A), and pseudouridine (Ψ), for which we provide flashcards (Figs. 1–4) summarizing their most important features and disease associations, and a comprehensive list of disease-related modified sites (Supplemental Table S1)
Summary
RNA molecules can undergo more than 170 different chemical modifications (Boccaletto et al 2018). The mouse orthologue ZFP217 has been shown to recruit the methyltransferase METTL3 into an inactive complex in embryonic stem cells (Aguilo et al 2015), and would cooperate with ALKBH5 in negatively regulating m6A levels and promoting breast tumorigenesis Both high and deficient m6A levels might influence global expression programs that lead to malignant phenotypes, and the crosstalk among m6A readers, erasers and writers critically regulates the expression of key transcripts to maintain cellular homeostasis (Panneerdoss et al 2018). Further work will be necessary to elucidate the mechanism of 2′-O-Me deposition and understand whether specific factors can act on all RNA species
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