A mark of disease: how mRNA modifications shape genetic and acquired pathologies

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.

MODOMICS: a database of RNA modification pathways. 2021 update

“…Moreover, the growing amount of information concerning modified nucleosides in RNA has improved the understanding of their function. Changes in RNA modifications have been recognized as the cause of various human diseases, including cancer, immune disorders, and neuromuscular defects ( 14–17 ). Consequently, improved understanding of the properties of RNAs with modified residues has allowed their use to develop RNA therapeutics, e.g., to improve the properties of RNA vaccines ( 18–20 ).…”

Functional interplay within the epitranscriptome: Reality or fiction?

“…[ 37,38 ] Given the widespread role of m 6 A in mRNA metabolism it is not surprising that its alteration has been linked to numerous developmental and physiological defects in human. [ 2,39 ]…”

“…[1] RNA modifications can control every aspect of RNA metabolism and their dysregulations have been associated with a wide range of physiological alterations and numerous diseases, including neurological diseases, metabolic disorders, and cancer. [2][3][4][5] The dynamic nature of some modifications is important to control gene expression upon developmental and environmental changes. [6][7][8] tRNAs are the most modified RNA species with up to 25% of all nucleotides carrying a chemical adduct.…”

The Identification of Two RNA Modification Patterns and Tumor Microenvironment Infiltration Characterization of Lung Adenocarcinoma

“…RNA modification induced by "writers" is the main contributor to post-transcriptional regulation of gene expression, and can occur in all RNA species, including messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs) (Destefanis et al, 2021). Some of the known disorders of RNA modification and RNA modification "writers" have been found to be associated with various types of cancers, including breast cancer, bladder cancer, and leukemia (Jonkhout et al, 2017).…”