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

Shi, Hanhan; Chai, Peiwei; Jia, Renbing; Fan, Xianqun

doi:10.1186/s12943-020-01194-6

Table 2 mRNA modifications regulate the physiological process from transcription to translation

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

Modifications		Process	Enzymes involved	Description	Ref
m⁶A RNA modification		mRNA splicing	HNRNPC	HNRNPC modulates the splicing of mRNAs by changing RNA structure and regulating the combination of RNA and reader	[10]
			HNRNPG	HNRNPG cooperates with modified pre-mRNA and the phosphorylated C-terminal domain of RNA polymerase II to regulate splicing	[47]
			FTO	FTO prefers to bind to introns of nascent mRNA	[48]
			ALKBH5	ALKBH5 relates to splicing factors tightly according to the analysis of immunofluorescence	[11]
		mRNA export	METTL3	METTL3 regulates the export of mature mRNA by modulating clock genes Per2 and Arntl	[49]
			YTHDC1	YTHDC1 mediates the export of decorated mRNA by interacting with SRSF3 and regulating the combination of SRSF3 an NXF1 on RNA	[50]
			ALKBH5	Knockdown of ALKBH5 leads to acceleration in mRNA export	[11]
		mRNA stability	ALKBH5	The stability of mRNA was decreased slightly in RNA lacking ALKBH5	[11]
			N.A.	Neighbouring sites of m⁶A and HuR weaken the function of HuR and increase the instability of mRNA	[52]
			N.A.	ELAV1/HuR, which is one of m⁶A-binding proteins and stabilizes transcripts with the cooperation of the ARE domain	[53]
		mRNA translation	YTHDF2	YTHDF2 regulates translation by transferring the bound RNA from the translatable pool to processing bodies to promote mRNA decay	[12]
				YTHDF2 induces the dysfunction of FTO in the 5'UTRs and contribute to promoting cap-independent translation	[28]
			YTHDF1	YTHDF1 increases the efficiency of translation by binding to m⁶A	[37]
			YTHDF3	YTHDF3 interacts with ribosomal proteins along with YTHDF1 to regulate translation	[54]
			YTHDF3	YTHDF3 decays of convinced translation related region in mRNA together with YTHDF2	[55]
			METTL3	When knocking out METTL3 in mESCs and Ebs, the translation efficiency is increased	[57]
			METTL3	METTL3 recruits eIF3 to the initiation complex directly and enhance translation level	[56]
m¹A RNA modification		mRNA stability	N.A.	m¹A in highly structured or GC-rich regions of 5'UTRs alters mRNA structural stability by modifying the predicted secondary structure	[61, 62]
		mRNA translation	N.A.	m¹A upregulated translation by depressing binding of releasing factor	[26]
			N.A.	m¹A prevents effective translation of CDS in mt-mRNA	[65]
			N.A.	The protein level would be superior when the transcript was modified by m¹A at/around the initiation codon	[69]
m⁵C RNA modification		mRNA export	ALYREF	ALYREF adjusts the export of transcripts by recognizing the unique RNA-binding motif	[77]
		mRNA translation	NSUN2	Deleting NSUN2 in HDFs can induce the elevation of p27, and overexpressing NSUN2 induces the opposite outcome	[79]
			NSUN2	m⁵C catalysed by NSUN2 in 3'UTRs of p21 mRNA coordinates with m⁶A methylated by METTL3/METTL14 together to enhance p21 expression	[80]
			N.A.	Translation diminishes significantly in both bacterial whole-cell extracts and HeLa cell extracts when m⁵C modifies the coding regions of mRNA	[27, 81]
			N.A.	m⁵C found on IL-17A mRNA can promote the translation of IL-17A	[82]
Other	hm⁵C	mRNA translation	N.A.	hm⁵C associates with translation activation in Drosophila	[69]
	Ψ	mRNA splicing	N.A.	Ψ, which is near the 3' splice site in the polypyrimidine tract, prevents pre-mRNA splicing by regulating U2AF	[83]
		mRNA stability	N.A.	The higher expression of heat shock-induced Pus7-dependent pseudouridylated transcripts in wild-type yeast than in Pus7-knockdown yeast indicates that Ψ has the capability to maintain stability of RNA	[84]
		mRNA translation	N.A.	Compared to U modifications located at similar sequences, Ψ-containing mRNA indicates an increase in translation levels of approximately 25%	[84]
			N.A.	Ψ doubles the expression of an unmodified transcript	[85]
			N.A.	When a separate Ψ modifies the special position of codon "UUU", mRNA translation can be limited	[81]
	I	mRNA structure	N.A.	I fastens pairs of nucleotides to influence the native secondary structure of mRNA	[86]
	I	mRNA translation	N.A.	Guanosine, adenosine and uracil are the products decoded from I by the translation machinery	[87]
	U	Protein expression	N.A.	Protein level alterations accompany C-to-U editing of RNA	[88]
	2'-O-Me	Viral RNA infection	N.A.	2'-O-Me-modified viral RNA disrupts native host antiviral responses by escaping suppression mediated by IFIT	[89]
	2'-O-Me	mRNA translation	N.A.	2'-O-Me modifies specific regions of mRNA that are translated to glutamate, lysine and glutamine, hinting that 2'-O-Me has the potential to affect translation efficiency	[90]

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