The Repertoire of RNA Modifications Orchestrates a Plethora of Cellular Responses

Abstract

Although a plethora of DNA modifications have been extensively investigated in the last decade, recent breakthroughs in molecular biology, including high throughput sequencing techniques, have enabled the identification of post-transcriptional marks that decorate RNAs; hence, epitranscriptomics has arisen. This recent scientific field aims to decode the regulatory layer of the transcriptome and set the ground for the detection of modifications in ribose nucleotides. Until now, more than 170 RNA modifications have been reported in diverse types of RNA that contribute to various biological processes, such as RNA biogenesis, stability, and transcriptional and translational accuracy. However, dysfunctions in the RNA-modifying enzymes that regulate their dynamic level can lead to human diseases and cancer. The present review aims to highlight the epitranscriptomic landscape in human RNAs and match the catalytic proteins with the deposition or deletion of a specific mark. In the current review, the most abundant RNA modifications, such as N6-methyladenosine (m⁶A), N5-methylcytosine (m⁵C), pseudouridine (Ψ) and inosine (I), are thoroughly described, their functional and regulatory roles are discussed and their contributions to cellular homeostasis are stated. Ultimately, the involvement of the RNA modifications and their writers, erasers, and readers in human diseases and cancer is also discussed.

Keywords: alternative splicing; erasers; m5C; m6A; mRNA stability; post-transcriptional modifications; readers; translation efficiency; writers; Ψ.

Figure 1

Venn diagram demonstrating the number of common RNA modifications that exist among many classes of RNA molecules, including tRNAs, mRNAs, and rRNAs, as well as snRNAs.

Figure 2

Common eukaryotic mRNA modifications that have been identified. The abundancy of each modification is strictly regulated by (a) “writers”, proteins that incorporate the specific modification in specific mRNA sites, (b) “erasers”, which catalyze the removal of a specific modification from the mRNA and (c) “readers”, which interact with specific modifications to regulate a wide spectrum of cellular processes.

Figure 3

Graphical representation of the identified nucleotide modifications in eukaryotic tRNAs and their corresponding position in the tRNA sequence.

Figure 4

Schematic demonstration of the detected RNA modifications in human 5.8S RNA, as well as their respective positions in the RNA sequence.