Novel insight into the regulatory roles of diverse RNA modifications: Re-defining the bridge between transcription and translation

Abstract

RNA modifications can be added or removed by a variety of enzymes that catalyse the necessary reactions, and these modifications play roles in essential molecular mechanisms. The prevalent modifications on mRNA include N6-methyladenosine (m⁶A), N1-methyladenosine (m¹A), 5-methylcytosine (m⁵C), 5-hydroxymethylcytosine (hm⁵C), pseudouridine (Ψ), inosine (I), uridine (U) and ribosemethylation (2'-O-Me). Most of these modifications contribute to pre-mRNA splicing, nuclear export, transcript stability and translation initiation in eukaryotic cells. By participating in various physiological processes, RNA modifications also have regulatory roles in the pathogenesis of tumour and non-tumour diseases. We discussed the physiological roles of RNA modifications and associated these roles with disease pathogenesis. Functioning as the bridge between transcription and translation, RNA modifications are vital for the progression of numerous diseases and can even regulate the fate of cancer cells.

Keywords: RNA modifications; diseases; m1A; m5C; m6A.

Fig. 1

Chemical structures of mRNA modifications. Chemical structures in eukaryotic mRNA including m⁶A, m¹A, m⁵C, hm⁵C, Ψ, I, U and 2’-O-Me

Fig. 2

Locations of chemical modifications in mRNA. Chemical RNA modifications are shown in mRNA with their approximate distribution in transcripts. m⁶A with a widespread distribution prefers to be located in the consensus motif in the 3’UTRs as well as the 5’UTRs, which closely correlate with translation. Although m¹A-containing mRNA is 10 times less common than m⁶A-containing mRNA, m¹A is discovered in every segment of mRNA, including the 5’UTRs, CDS and 3’UTRs and mostly in highly structured 5’UTRs. Analogous to m¹A, m⁵C can occur in coding and non-coding regions of mRNA, especially in GC-rich regions. Nevertheless, m⁵C within different positions regulates transcription differently. Tet-family enzymes prefer to oxidize m⁵C modifications in coding regions, so hm⁵C has a greater possibility of being present in CDS. Subsequently, Ψ is demonstrated to have a diversified location, whereas I is present at a large number of sites in the CDS, and U accumulates in 3’UTRs. 2’-O-Me focuses on decorating specific regions of mRNA that encode given amino acids. Additionally, as reversible modifications, most have their own readers, writers and erasers

Fig. 3

m⁶A RNA modification regulates physiological processes in cell. m⁶A RNA modification in mRNA plays an essential role in cellular processes, including mRNA splicing, mRNA export, mRNA stability and mRNA translation. Both readers (HNRNPC and HNRNPG) and erasers (FTO and ALKBH5) can modulate the splicing of mRNA. After splicing and combination, pre-mRNA evolves into mature mRNA. Regulated by ALKBH5, METTL3 and YTHDC1, mature mRNA is exported from the nucleus to the cytoplasm. Once exported to the cytoplasm, both ALKBH5 and ELAV1/HuR can maintain mRNA stability. Finally, numerous enzymes contribute to the process of translation. YTHDF1, YTHDF2, YTHDF3, FTO and METTL3 together with eIF3 can regulate translation with different mechanisms individually

Fig. 4

Regulatory roles of RNA modifications in pathogenesis. Applying physiology to pathology, RNA modifications redefine the bridge between transcription and translation and regulate disease pathogenesis. In AML, METTL3 and METTL14 enhance the expression of m⁶A modifications as well as the BCL2, PTEN, SP1, MYB and MYC genes, which lead to tumour progression. Simultaneously, FTO decreases m⁶A abundance on ASB2 and RARA mRNA. In digestive system tumours, aberrant METTL3 leads to aberrant expression of HDGF, ZMYM1, SEC62 and SOCS2, which can regulate cancer cells in the stomach, liver and pancreas, respectively. In lung cancer, METTL3 enhances the translation of EGFR and TAZ, whereas SUMOylated METTL3 promotes NSCLC; aberrant YTHDF2 enhances the expression of 6PGD in lung cancer, and overexpressed FTO stabilizes and accelerates the expression of USF7 and MZF1 as well. In glioblastoma, METTL3, METTL14 and ALKBH5 promote the expression of ADAM19 and FOXM1 and predict poor prognosis. In prostate cancer, aberrant YTHDF2 suppresses proliferation and migration. In bladder cancer, METTL3 reduces the expression of PTEN and tumorigenesis of cancer. In the reproductive system, METTL3 and FTO contribute to the aberrant expression of KLF4, NANOG, HBXIP, BNIP3 and β-catenin, which induce proliferation of breast cancer and chemoradiotherapy resistance of cervical cancer separately. In sensory organs, YTHDF1 accelerates the translation of methylated HINT2 and inhibits the progression of ocular melanoma. Aberrant eraser ALKBH3 reduces m¹A modifications, leads to aberrant expression of CSF-1, ErbB2 and AKT1S1, and induces the progression of ovarian cancer, breast cancer, gastrointestinal cancer and urothelial cancer. In UCB, YBX1 recognizes m⁵C-modified HDGF mRNA and leads to tumour advancement. Upregulated USUN2 is detected in breast cancer. Ultimately, aberrant ADAR1 edits AZIN1, BLCAP, and DHFR separately, which leads to hepatocellular carcinoma, cervical cancer and breast cancer. Additionally, together with Ψ, I and U, DKC1, ADAR1 and UPP1 can function as biomarkers to indicate prostate cancer progression, LUAD presentation and thyroid carcinoma status