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Open Access 01.12.2020 | Review

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

verfasst von: Hanhan Shi, Peiwei Chai, Renbing Jia, Xianqun Fan

Erschienen in: Molecular Cancer | Ausgabe 1/2020

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.

Hanhan Shi and Peiwei Chai contributed equally to this work.

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2’-O-Me

Ribose-methylation

3’UTR

3’ untranslated region

5’UTR

5’ untranslated region

6PGD

6-phosphogluconate dehydrogenase

Pseudouridine

ADAM19

A disintegrin and metallopeptidase domain 19

ADAR

Adenosine deaminases acting on RNA

ADARB1

Adenosine deaminase RNA-specific B1

AKT

AKT serine/threonine kinase

AKT1S1

AKT1 substrate 1

ALKBH5

α-ketoglutarate-dependent dioxygenase alkB homolog 5

ALYREF

Aly/REF export factor

AML

Acute myeloid leukaemia

Arntl

Aryl hydrocarbon receptor nuclear translocator-like

ARE

AU-rich element

ASB2

Ankyrin repeat and SOCS box-containing 2

A-to-I editing

Adenosine-to-inosine RNA editing

AZIN1

Antizyme inhibitor 1

BCL2

B cell leukaemia

BCSC

Breast cancer stem cell

BLCAP

Bladder cancer-associated protein

BNIP3

BCL2 interacting protein 3

CDS

Coding sequence

CEBPZ

CCAAT enhancer binding protein zeta

CNV

Copy number variation

CPE

Cytoplasmic polyadenylation element

CSCC

Cervical squamous cell carcinoma

CSF-1

Colony stimulating factor 1

C-to-U editing

Cytidine-to-uridine RNA editing

DAA

3-deazaadenosine

DHFR

Dihydrofolate reductase

DKC1

Dyskerin pseudouridine synthase 1

DNMT

DNA methyltransferase homologue

Embryoid body

EGFR

Epidermal growth factor receptor

eIF3

Eukaryotic initiation factor 3

ELAV1

ELAV-like RNA-binding protein 1

EMT

Epithelial-mesenchymal transition

Fasn

Fatty acid synthase

FLT3

Fms-related tyrosine kinase 3

FMR1

Fragile X mental retardation 1

Fn14

Fibroblast growth factor-inducible 14

FOXM1

Forkhead box M1

FTO

Fat mass and obesity-associated protein

Gastric cancer

HBXIP

Hepatitis B X-interacting protein

HCC

Hepatocellular carcinoma

HDF

Human diploid fibroblast

HDGF

Hepatitis B X-interacting protein

HIF

Hypoxia inducible factor

hm⁵C

5-hydroxymethylcytosine

HNRNP

Heterogeneous nuclear ribonucleoprotein

HuR

Hu antigen R

IFIT

IFN-induced proteins with tetratricopeptide repeats

IGF2BP

Insulin-like growth factor 2 mRNA-binding protein

IL-17A

Interleukin-17A

IRE

Iron-responsive element

KLF4

Kruppel like factor 4

LRPPRC

Leucine-rich pentatricopeptide repeat-containing

LUAD

Lung adenocarcinoma

LUSC

Lung squamous cell carcinoma

m¹A

N1-methyladenosine

m⁶A

N6-methyladenosine

m⁵C

5-methylcytosine

Meclofenamic acid

MAPK

Mitogen-activated protein kinase

mESC

Mouse embryonic stem cell

METTL3

Methyltransferase-like 3

METTL14

Methyltransferase-like14

MiR-4429

MicroRNA 4429

MLL

Mixed lineage leukaemia

mRNA

Message RNA

mt-mRNA

Mitochondrial mRNA

mTOR

Mammalian target of rapamycin

MYB

Myeloblastosis oncogene

MYC

Myelocytomatosis oncogene

MZF1

Myeloid zinc finger 1

NANOG

Nanog homeobox

ND5

NADH

ubiquinone oxidoreductase core subunit 5

NOX-2-ROX

NADPH oxidase-2-reactive oxygen species

NPC

Neplanocin A

NPM1

Nucleophosmin 1

NSCLC

Non-small-cell lung cancer

NSUN

NOL1/NOP2/SUN domain

NXF1

Nuclear RNA export factor 1

Per2

Period circadian regulator 2

PHLPP2

PH domain and leucine rich repeat protein phosphatase 2

PML

Promyelocytic leukaemia

PODXL

Podocalyxin like

PTEN

Phosphatase and tensin homologue

Queuosine

Rheumatoid arthritis

RARA

Retinoic acid receptor alpha

RBM15

RNA-binding motif protein 15

rRNA

Ribosomal RNA

SAH

S- adenosylhomocysteine

SEC62

SEC62 homologue, preprotein translocation factor

snRNA

Small nuclearRNA

SOCS2

Suppressor of cytokine signalling 2

SOX2

SRY-box transcription factor 2

SP1

Sp1 transcription factor

SPI1

Spi-1 proto-oncogene

SRSF3

Serine and arginine rich splicing factor 3

STAT3

Signal transducer and activator of transcription 3

SUMO

Small ubiquitin-like modifier

T2DM

Type 2 diabetes mellitus

TAZ

Tafazzin

TRMT

tRNA methyltransferase

tRNA

Transfer RNA

TWEAK

TNF-like weak inducer of apoptosis

U2AF

U2 auxiliary factor

UCB

Urothelial carcinoma of the bladder

UPP1

Uridine phosphorylase 1

USP7

ubiquitin-specific protease 7

VEGF

Vascular endothelial growth factor

WTAP

Wilms tumour 1-associated protein

X-DC

X-linked dyskeratosis congenita

YAP

Yes-associated protein

YBX1

Y-Box binding protein 1

YTH

YT521-B homology

ZC3H13

Zinc finger CCCH-type containing 13

ZMYM1

Zinc finger MYM-type containing 1

ZNF217

Zinc finger protein 217

Introduction

In the 1950s, the first RNA nucleoside modification was identified [1]; since then, researchers have focused on updating the understanding of RNA modifications. At the very beginning, the 5’cap and the poly(A) tail, which represent cap and tail modifications, respectively, were discovered. However, with the limitations of technology, modifications of eukaryotic mRNA ends were considered the only post-transcriptional alterations to mRNA for a while. Fortunately, this situation did not last for a long time. Internal mRNA modifications have been investigated in succession in the last 50 years. The revealed mRNA modifications included but were not limited to N6-methyladenosine (m⁶A), N1-methyladenosine (m¹A), 5-methylcytosine (m⁵C), 5-hydroxymethylcytosine (hm⁵C), pseudouridine (Ψ), inosine (I), uridine (U) and ribose-methylation (2’-O-Me) [2‐4] (Figs. 1 and 2). m⁶A is the most abundant modification and was therefore thoroughly investigated [5].

Analogous to mRNA modification, we also identified many modifications on transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), such as queuosine (Q) [6]. Eukaryotic tRNAs contain, on average, over 10 modifications per molecule. From elementary isomerization or methylation to complicated modifications of ring structures, the number of tRNA modifications is the largest and has the widest chemical variety. Moreover, there are over 200 modifications on human rRNAs. Thus, their less complicated nature and greater abundance led to more investigations of tRNAs and rRNAs, even beyond mRNAs. Early studies have demonstrated that this variety of modifications leads to extra cellular functions for diverse RNA species [7].

The regulatory role of RNA modifications

Modifications on different RNAs were found to regulate various cellular processes. Researchers demonstrated that these modifications can initiate translation, stabilize transcripts, splice pre-mRNA, facilitate nuclear export, etc. [8‐12]. With respect to RNA modifications and technological advances in high-throughput sequencing and mass spectrometry, the mechanisms of different cellular processes influenced by RNA modifications are underexplored, including the less ubiquitous modifications on rare RNA species. tRNAs, which have the greatest number of types of different chemical modifications, regulate molecular mechanisms by selecting and protecting the reading framework, promoting tRNA decoding capability as well as changing codon-anti-codon connections [13‐17]. Moreover, the functions of 2’-O-Me, Ψ and m⁵C, which are abundant in rRNA, have been investigated in detail. Without any doubt, mRNA modifications play roles in modulating molecular mechanisms. Subsequently, RNA modifications contribute to tumorigenesis by regulating cell survival, differentiation, migration and drug resistance [18].

m⁶A RNA modification

Introduction to m⁶A RNA modification

m⁶A accounts for approximately 0.2~0.6% of total adenosines in mammalian RNA [2, 5]. General m⁶A modifications occur in mammals, plants, bacteria and even other types of eukaryotic RNA [19‐22]. In addition to their widespread distribution, there is no less than 1-2 methylated adenosines in every single mRNA [23]. Studies have reported that m⁶A is located in the 3’ untranslated region (3’UTR), predominantly in a consensus motif, GGm⁶ACU [24‐26]. Recently, m⁶A was also found in the 5’ untranslated region (5’UTR), a region that closely correlates with translation. It has been reported that methylated adenosine in the 5’UTR of mRNA can support cap-independent translation commencement and can increase translation [27, 28].

As a reversible mRNA modification, m⁶A has its own writers, readers and erasers. Methyltransferase-like 3 (METTL3) was the first demonstrated m⁶A writer [29]. In addition to METTL3, other proteins possessing methyltransferase (MTase) capability were recently identified, including methyltransferase-like 14 (METTL14), Wilms tumour 1-associated protein (WTAP), RNA-binding motif protein 15 (RBM15), KIAA 1429 and zinc finger CCCH-type containing 13 (ZC3H13) [30‐33]. By binding to mRNA, readers, such as members of the YT521-B homology (YTH) domain family of proteins (YTHDF1, YTHDF2, YTHDF3, YTHDC1 and YTHDC2) and heterogeneous nuclear ribonucleoprotein (HNRNP) proteins (HNRNPA2B1 and HNRNPC) can execute the physiological functions of the modification [8, 10, 12, 34‐38]. Additionally, eukaryotic initiation factor 3 (eIF3), insulin-like growth factor 2 mRNA-binding proteins (IGF2BP1, IGF2BP2 and IGF2BP3), fragile X mental retardation 1 (FMR1) and leucine-rich pentatricopeptide repeat-containing (LRPPRC) all can read m⁶A modifications [39, 40]. Both fat mass and obesity-associated protein (FTO) and alkB homologue 5 (ALKBH5) are erasers of m⁶A modifications [11, 41, 42].

Regulatory role of m⁶A RNA modification in molecular functions

Accumulation of pre-mRNA and diminution of mature mRNA in cyclo-leucine-treated avian sarcoma virus-infected cells and neplanocin A (NPC)-treated SV40 RNA demonstrate that m⁶A is essential in pre-mRNA splicing [43, 44]. Both cyclo-leucine and NPC are inhibitors of methylation that can be used to investigate m⁶A [45, 46]. Subsequently, MTases and demethylases might be involved in regulating RNA splicing. By changing RNA structure and regulating the combination of RNA and reader proteins, HNRNPC can modulate the splicing of m⁶A-containing mRNAs [10]. More recently, by relying on the RGG region in the low-complication region of HNRNPG, a reader was reported to cooperate with modified pre-mRNA and the phosphorylated C-terminal domain of RNA polymerase II to modulate splicing [47]. Moreover, FTO is vital to mRNA splicing because it prefers to bind to introns of nascent mRNA [48]. Another splicing-related eraser is ALKBH5. Immunofluorescence analysis revealed that ALKBH5 was tightly related to splicing factors [11].

Writers, readers and erasers can all regulate mRNA export. By modulating the clock genes Per2 and Arntl, METTL3 regulates the export of mature mRNA [49]. By interacting with SRSF3 and regulating the combination of SRSF3 and NXF1 on RNA, YTHDC1 mediates the export of modified mRNA [50]. Subsequently, knockdown of ALKBH5 leads to acceleration of mRNA export, suggesting that m⁶A is essential to regulating mRNA export [11].

AU-rich element (ARE), iron-responsive element (IRE) and cytoplasmic polyadenylation element (CPE) represent functional domains and are responsible for mRNA decay in 3’UTRs [51]. Coincidentally, m⁶A accumulates in 3’UTRs. Thus, the neighbouring sites of m⁶A and Hu antigen R (HuR), which is supposed to bind ARE to increase the stability of mRNA, lead to weak HuR function and mRNA instability [52]. However, ELAV1/HuR, a potential m⁶A-binding protein, can stabilize transcripts with the cooperation of the ARE domain [53]. Subsequently, it was reported that the stability of mRNA was decreased slightly in cells lacking ALKBH5 [11].

The YTH domain family of proteins has a conserved m⁶A-binding pocket so that these proteins can tightly bind to m⁶A in a consensus sequence and directly transcribe the molecule [12, 26, 34‐38]. Specifically, YTHDF2 accelerates mRNA decay by transferring RNA from the translatable pool to processing bodies [12]. Under heat shock conditions, dysfunction of FTO in 5’UTRs, which is regulated by YTHDF2, contributes to the promotion of cap-independent translation [28]. Moreover, YTHDF1 can increase the efficiency of translation by binding m⁶A [37]. Subsequently, YTHDF3 can regulate translation by both interacting with ribosomal proteins with bound YTHDF1 and by decaying the translation-related mRNA region with bound YTHDF2 [54, 55]. However, METTL3 can regulate translation flexibly because it can either recruit eIF3 to the initiation complex directly to increase translation or can inhibit translation efficiency [56, 57]. The translation efficiency is increased when METTL3 is knocked out in mouse embryonic stem cells (mESCs) and embryoid bodies (EBs) [57] (Fig. 3).

m¹A RNA modification

Introduction of m¹A RNA modification

m⁶A has been reported to occur in DNA from a minor cluster of microorganisms and in RNA from an extensive range of organisms, and additionally, m¹A was identified in the 1960s [58]. Rather than accumulating in mRNA, m¹A is predominant in tRNA and rRNA, but we recently determined that it also exists in mRNA [59, 60]. However, m¹A-containing mRNA is 10 times less common than m⁶A-containing mRNA [61, 62]. In tRNA and rRNA, m¹A conserves the tertiary structure and affects translation [63, 64]. In mRNA, m¹A has been discovered in every mRNA segment, including the coding sequence (CDS), 5’UTR and 3’UTR, although it is mostly found in the highly structured 5’UTR [62]. As a result, the location of the m¹A methylated atom determines the function and mechanism of this kind of modification.

Because the distribution of m¹A is imbalanced, the large number of m¹A modifications on tRNA results in more tRNA m¹A MTases than writers on mRNA. However, TRMT6/61A recognized a T-loop-like structure with a GUUCRA tRNA-like motif in mRNAs and decorated it with the m¹A modification, TRMT61B installed m¹A in mt-mRNA transcripts, and TRMT10C methylated the 1374 position of ND5 mt-mRNA [65, 66]. All of these phenomena contribute to tRNA m¹A MTases and can function as mRNA writers. By binding to m¹A-bearing RNA, YTHDF1, YTHDF2, YTHDF3 and YTHDC1 act as readers [67]. Subsequently, similar to ALKBH5 functioning as an eraser for m⁶A, ALKBH1 and ALKBH3 were able to demethylate m¹A mRNA modifications [62, 68].

Regulatory role of the m¹A RNA modification in molecular functions

It has been reported that m¹A methylation occurs in highly structured or GC-rich regions of 5’UTRs (which is also the most frequent location) and may modify the predicted secondary structure, which hints at the potential of m¹A to alter mRNA structural stability [61, 62].Moreover, m¹A methylation can not only increase translation by decreasing the binding of the releasing factor but also prevent effective translation of m¹A-containing CDS in mt-mRNA [26, 65]. Ultimately, it has been reported that the protein level is higher when a transcript carries the m¹A modification around the initiation codon [69].

m⁵C RNA modification

Introduction of the m⁵C RNA modification

m⁵C is a long-standing DNA modification that is essential for gene expression and epigenetic regulation [70, 71]. However, it can also be found in RNA. Although the m⁵C RNA modification can appear in both coding and non-coding regions, it has been reported to accumulate in the UTRs of mRNA and especially prefers to be located in GC-rich regions [72]. Since a number of studies have investigated the function of m⁵C in specific mRNAs, we concluded that m⁵C modifications in different locations (5’UTRs, 3’UTRs, coding regions) exert different transcriptional regulation activities [73].

It was revealed that m⁵C RNA modifications are catalysed by the NOL1/NOP2/SUN domain (NSUN) family of proteins (NSUN1, NSUN2, NSUN3, NSUN4, NSUN5, NSUN6 and NSUN7) as well as the DNA methyltransferase (DNMT) homologue DNMT2 [74‐76]. However, among such diversified writers, only NSUN2 can install m⁵C on mRNA because rest of these proteins are writers of tRNAs and rRNAs. Subsequently, Aly/REF export factor (ALYREF), a specific mRNA m⁵C-binding protein that can read modifications, was identified as a reader of m⁵C [77]. According to liquid chromatography-tandem mass spectrometry analysis, YBX1 was defined as the other m⁵C reader that can maintain the stability of target mRNA [78]. Knowledge is limited about the protein factors responsible for removing modifications (Table 1).

Table 1

Writers, readers and erasers of the predominant mRNA modifications

RNA modification	Writers	Readers	Erasers
m⁶A	METTL3; METTL14; WTAP; RBM15; ZC3H13	YTH domain family of proteins (YTHDF1, YTHDF2, YTHDF3, YTHDC1 and YTHDC2); HNRNP (HNRNPA2B1 and HNRNPC); eIF3; IGF2BP (IGF2BP1, IGF2BP2, and IGF2BP3); FMR1; LRPPRC	FTO; ALKBH5
m¹A	TRMT6/61A; TRMT61B; TRMT10C	YTHDF1; YTHDF2; YTHDF3; YTHDC1	ALKBH1; ALKBH3
m⁵C	NSUN2; DNMT2	ALYREF; YBX1	N.A.

Regulatory role of the m⁵C RNA modification in molecular functions

ALYREF, the reader of m⁵C, can adjust the export of transcripts by recognizing a unique RNA-binding motif [77]. Subsequently, NSUN2 adds m⁵C to both p27 mRNA at cytosine C64 in the 5’UTR and p21 mRNA in the 3’UTR [79, 80]. Deleting NSUN2 in human diploid fibroblasts (HDFs) can induce the elevation of p27, and overexpressing NSUN2 results in contrasting outcomes [79]. These results suggest that the m⁵C catalysed by NSUN2 in the 5’UTRs can limit the translation of p27. However, the m⁵C modifications added by NSUN2 to the 3’UTRs of p21 mRNA coordinate with the m⁶A modifications added by METTL3/METTL14 together to enhance the expression of p21 [80]. With regard to m⁵C modification in mRNA coding regions, it was revealed that in both bacterial whole-cell extracts and HeLa cell extracts, m⁵C could diminish translation significantly [27, 81]. Moreover, we demonstrated that when the m⁵C modification was present on interleukin-17A (IL-17A) mRNA, this modification could promote the translation of IL-17A [82]. The results of the above investigations revealed that the m⁵C RNA modification affects the expression of proteins by regulating both translation efficiency and transcript export (Table 2).

Table 2

mRNA modifications regulate the physiological process from transcription to 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]

Other RNA modifications

hm⁵C

m⁵C can be oxidized into hm⁵C via the function of the Tet-family enzymes [91‐93]. Moreover, hMeRIP-seq showed that Tet-family enzymes prefer to oxidize m⁵C modifications in coding regions; these results indicate that hm⁵C is highly likely to be located in the introns and exons of coding transcripts. However, in contrast to m⁵C methylation in the coding regions of mRNA, which plays a negative role in translation, hm⁵C tends to associate with translation activation in Drosophila [69].

Ψ

As hm⁵C is analogous to the oxidization of m⁵C, Ψ is produced by the isomerization of U. Ψ is the most abundant RNA modification and prefers to accumulate in tRNA and rRNA; however, it has also been reported to be present on mRNA and snRNA [94, 95]. Interestingly, the number of Ψ sites in mRNA ranges from 96 to 2084 in humans [84, 96‐98].

However, by regulating U2 auxiliary factor (U2AF), Ψ, which is near the 3’ splice site in the polypyrimidine tract, prevents pre-mRNA splicing [83]. Expression of heat shock-induced Pus7-dependent pseudouridylated transcripts is higher in wild-type yeast than in Pus7-knockdown yeast and indicates that Ψ has the capability to maintain RNA stability [84]. Nevertheless, modifications were examined at similar sequences, and compared to U-containing mRNA, Ψ-containing mRNA experienced an increase in translation by approximately 25% [84]. Such modifications could double the expression of translation when compared to blank control transcript without any modification [85]. Although Ψ can promote translation and enhance the lifespan of RNA, it has negative effects on protein expression [85]. It has been reported that Ψ-containing mRNA exhibits a 30% decrease in protein expression. Specifically, bacterial mRNA translation can be limited when a separate Ψ modification is present at a given position of codon “UUU”, especially at the third codon position [81]. Moreover, both in vitro and in vivo, the Ψ modification might change the nonsense codons into sense codons [99, 100]. Above all, some of these investigations were conducted by Ψ in artificial mRNA, and the function of Ψ in biological mRNA has yet to be elucidated.

I and U

Catalysed by adenosine or cytidine deaminating enzymes, RNA editing is a kind of programmed alteration [101]. However, rather than permanent DNA mutations or reversible RNA modifications, RNA editing has its own limited lifespan and results in more permanent modification [102].

Adenosine-to-inosine RNA editing (A-to-I editing), also called I, is catalysed by adenosine deaminases acting on RNA (ADARs) [101, 103, 104]. Recently, 1741 I sites have been reported in CD regions of transcripts from RNA-seq data of different human tissues [105]. Moreover, it has been reported that ADAR1 and ADAR2 act only on double-stranded regions, which limits the areas of mRNA that I can modify [106]. I can fasten pairs of nucleotides; thus, this widespread modification in metazoan mRNA can influence the native secondary structure of mRNA [86]. An in vitro translation system was implemented to scientifically test the decoding of I, revealing that guanosine, adenosine and uracil are the products decoded from I by translation machinery [87].

However, with regard to cytidine-to-uridine RNA editing (C-to-U editing), also called U, it has been reported that U accumulates in 3’UTRs, and over 70 new sites have been discovered by transcriptome-wide research [88, 107]. Subsequently, after exploring several intestinal mRNAs, it was revealed that the protein level is altered by C-to-U editing of RNA [88]. However, there is little research on the relationship between the expression of transcripts and U. The biological influence of U has yet to be investigated.

2’-O-Me

Unlike how I and U are modifications on a base, 2’-O-Me is methylation of ribose at the 2’ position [59]. It was revealed that by escaping the suppression mediated by IFN-induced proteins with tetratricopeptide repeats (IFIT), 2’-O-Me-modifiedviral RNA disrupts native host antiviral responses [89]. Surprisingly, 2’-O-Me focuses on modifying specific regions of mRNA where the encoded amino acids are immobilized; these amino acids include glutamate, lysine and glutamine [90]. This phenomenon hints at the hypothesis that 2’-O-Me has the potential to affect translation efficiency, which has previously been demonstrated in bacterial mRNA [81].

Regulatory roles of RNA modifications in pathogenesis

Aberrant m⁶A RNA modifications in diseases

In acute myeloid leukaemia (AML), FTO decreases m⁶A abundance on ASB2 and RARA mRNA in several certain subtypes of AML, including t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations [41, 108]. Moreover, by constraining YTHDF2-mediated decay, FTO decreases m⁶A frequency on MYC mRNA [109], METTL3 promotes translation of BCL2 and PTEN mRNA by upregulating the m⁶A levels and supports expression of SP1 by binding to the unique region with the help of the transcription factor CEBPZ [110, 111], and METTL14 enhances mRNA expression of MYB and MYC [112]. All pathological pathways contribute to carcinogenesis in AML. According to the datasets from The Cancer Genome Atlas, nearly 10.5% of AML patients carry copy number variations (CNVs) of ALKBH5, which predicts poor prognosis and p53 mutations [113].

In gastric cancer (GC), METTL3 can cause m⁶A to accumulate on HDGF mRNA, which indicates proliferation and poor prognosis and enhances the stability of zinc finger MYM-type containing 1 (ZMYM1) mRNA so that it accelerates epithelial-mesenchymal transition (EMT) and metastasis [114, 115]. However, METTL3 can also reduce m⁶A on SEC62 with the help of MiR-4429 [116]. In hepatocellular carcinoma (HCC), METTL3 enhances the degradation of m⁶A-containing SOCS2 mRNA together with YTHDF2 [117]. Additionally, YTHDF2 supresses ERK/MAPK signalling cascades and cell proliferation by destabilizing the EGFR mRNA [118]. Regarding clinical diagnosis, downregulated METTL14 is detected in HCC patients, and the level of expression in metastatic HCC is further decreased [119]. In pancreatic cancer, m⁶A and METTL3 protein and mRNA levels were much higher in tumour specimens than in para-cancerous specimens [120]. Meanwhile, upregulation of YTHDF2 destabilizes YAP mRNA by initiating the AKT/GSK3β/cyclin D1 pathway, which promotes proliferation and inhibits the migration of pancreatic cancer [121].

In lung cancer, METTL3 enhances the translation of EGFR and TAZ mRNA [56]. Furthermore, SUMOylated METTL3 promotes non-small-cell lung cancer (NSCLC) by diminishing the amount of m⁶A [122]. Moreover, YTHDF2 enhances the translation of 6-phosphogluconate dehydrogenase (6PGD) mRNA by binding to a given region in lung cancer cells [123]. Additionally, FTO is overexpressed in human NSCLC tissues and stimulates lung cancer by stabilizing and increasing the expression of ubiquitin-specific protease 7 (USP7) [124]. In lung squamous cell carcinoma (LUSC), overexpressed FTO accelerates oncogene MZF1 expression by diminishing m⁶A and stabilizing mRNA as well [125, 126].

For the nervous system, decreased levels of METTL3 or METTL14 determine the diminution of m⁶A on ADAM19 mRNA, which promotes protein expression [127, 128]. Conversely, increased levels of ALKBH5 lead to decreased levels of m⁶A on FOXM1 mRNA and enhance protein expression [129]. Consequently, a high level of ALKBH5 predicts poor prognosis [130]. However, both pathways can contribute to glioblastoma. Subsequently, overexpressed METTL3 recruits HuR to modified SOX2 mRNA and enhances radio-resistance. Playing an oncogenic role in glioblastoma, METTL3 hints at poor prognosis and a potential therapeutic strategy as well [131].

In prostate cancer, reduced YTHDF2 elevates m⁶A contents dramatically, which suppresses proliferation and migration [132]. In bladder cancer, increased METTL3 predicts poor survival because with the help of pri-miR221/222, upregulated METTL3 results in downregulated PTEN and tumorigenesis of cancer [133].

Aberrant m⁶A modification can also lead to carcinomas in the reproductive system. It has been reported that m⁶A on KLF4 and NANOG can be suppressed by the cooperation of ZNF217 and ALKBH5, especially in a HIF-dependent manner, so that it enhances the stability of mRNA and contributes to breast cancer in a hypoxic microenvironment [134, 135]. Increased METTL3 leads to enhancement of m⁶A on hepatitis B X-interacting protein (HBXIP) and proliferation of breast cancer stem cells (BCSCs) [136]. Moreover, elevated FTO leads to downregulated methylation and degradation of BNIP3. It is suggested that FTO enhances the colony formation and metastasis of breast cancer [137]; Nevertheless, in cervical squamous cell carcinoma (CSCC), high expression of FTO and low levels of β-catenin lead to chemoradiotherapy resistance, which hints that FTO is a potential target to increase the chemoradiotherapy sensitivity of CSCC [138]. In endometrial cancer, either mutated METTL14 or reduced METTL3 limits the expression of m⁶A. However, limited m⁶A activates the AKT signalling pathway and stimulates proliferation and tumorigenicity by decreasing the negative AKT regulator PHLPP2 and increasing the positive AKT regulator mTORC2 [139].

Besides the regular cancers with high incidence referenced above, aberrant m⁶A modifications also play roles in sensory organs. The fate of ocular melanoma can be modulated by m⁶A modifications. With the help of YTHDF1, the translation of methylated HINT2 mRNA, a tumour suppressor of ocular melanoma, was significantly accelerated, meaning m⁶A modification obviously inhibits the progression of ocular melanoma. Moreover, investigation of ocular melanoma samples indicated that decreased m⁶A levels were highly associated with poor prognosis [140].

Aberrant m¹A RNA modification in diseases

Physiological functions lead to pathological impacts on diverse diseases. In ovarian and breast cancers, demethylation of m¹A by ALKBH3 induces increased modified CSF-1 mRNA, which contains m¹A in the 5’UTR near the translation initiation site. Hence, accumulated ALKBH3 means improved CSF-1 mRNA expression and invasion of cancer cells [141]. Subsequently, ALKBH3, considered the eraser of m¹A, tightly correlates with the mTOR pathway in gastrointestinal cancer and is attributed to the limited expression of ErbB2 and AKT1S1 after ALKBH3 knockdown; the downstream genes of m¹A are associated with cell proliferation according to Gene Ontology analysis [142]. Additionally, silencing of ALKBH3 arrests the cell cycle at the G1 phase and contributes to the progression, angiogenesis and invasion of urothelial carcinomas by modulating NADPH oxidase-2-reactive oxygen species (NOX-2-ROX) and TNF-like weak inducer of apoptosis (TWEAK)/Fibroblast growth factor-inducible 14 (Fn14)-VEGF signals [143]. As a classical chemical modification of mRNA, the pathological pathways of m¹A need to be elucidated.

Aberrant m⁵C RNA modification in diseases

Since m⁵C bridges transcription and translation, we propose a hypothesis that m⁵C can also regulate the pathological mechanisms of various diseases. For instance, diminishing NSUN2 leads to decreased levels of translation and an increased tumour initiating population in skin cancer [144]. In breast cancer, NSUN2 is reported to be upregulated as well at the mRNA and protein levels [145]. For patients with urothelial carcinoma of the bladder (UCB), m⁵C-modified 3’UTR in HDGF mRNA can be recognized by YBX1 and activate the oncogene of UCB [78]. m⁵C can also be regarded as a cancer biomarker because the amount of m⁵C RNA modification is increased in circulating tumour cells from patients with lung cancer [146].

Aberrant hm⁵C, Ψ, I, U and 2’-O-Me RNA modifications in diseases

Although the amounts of hm⁵C, Ψ, I, U and 2’-O-Me RNA modifications on mRNA are much lower than the three predominant types of modifications, their roles do not change and are vital to human disease. First, Ψ can function as a biomarker for prostate cancer because certain nucleolar RNAs (H/ACA snoRNAs) and the dyskerin (DKC1) protein can upregulate the transformation of U to Ψ and contribute to the advancement to cancer [147]. Regarded as the gene encoding the Ψ synthase, the mutation of DKC1 causes downregulated Ψ and X-linked dyskeratosis congenita (X-DC) [148]. The risk for cancer development is higher in patients with X-DC than those without gene mutation [149]. Besides, H/ACA snoRNAs are limited in acute leukaemia, lymphoma and multiple myeloma [150‐152].

Subsequently, edited AZIN1 stimulates a serine to glycine (S/G) conversion in HCC and leads to proliferation and poor prognosis [153, 154]. In HCC and in cervical cancer, increased editing of BLCAP activates the AKT/mTOR signalling pathway or STAT3, which can increase cell proliferation and limit apoptosis [155‐158]. In breast cancer, editing of DHFR transcripts at the 3’UTR by ADAR1 stabilizes the mRNA and enhances cell growth. Surprisingly, methotrexate, a chemotherapy agent, prevents cancer cell division by targeting DHFR. It is suggests that downregulated ADAR1 can contribute to methotrexate treatment [159]. In gastric cancer, ADAR2 edits the CDS of PODXL, which induces a histidine to arginine conversion. The relationship between reduced ADAR2 and increased malignancy hints that transcript editing is essential to prevent cancer progression [160]. Additionally, adenosine deaminase RNA-specific B1 (ADARB1), a special type of ADAR, is expressed at low levels in H358 and A549 lung adenocarcinoma (LUAD) cells, which suggests that I might be a potential target in diagnostic and prognostic progression for patients with LUAD [161].

Finally, uridine phosphorylase 1 (UPP1) is another enzyme that can reversibly catalyse the phosphorolysis of uridine to uracil [162, 163]. It has been reported that expression of UPP1 significantly depends on lymph node metastasis and tumour stage and size in patients with thyroid carcinoma [164] (Table 3, Fig. 4).

Table 3

Aberrant mRNA modifications in diseases

Modification	Disease	Enzyme	Target	Description	Ref
m⁶A	AML	FTO	ASB2/ RARA	FTO decreases m⁶A abundance on ASB2 and RARA mRNA in certain subtypes of AML and diminishes the amount of protein	[41, 108]
			MYC	FTO decreases m⁶A frequency on MYC mRNA by limiting YTHDF2-mediated RNA decay	[109]
		METTL3	BCL2/ PTEN	METTL3 promotes the translation of BCL2 and PTEN mRNA by upregulating m⁶A levels	[110]
		METTL3	SP1	METTL3 supports the expression of SP1 by binding to the unique region with the help of the transcription factor CEBPZ	[111]
		METTL 14	MYB/ MYC	METTL14 enhances the expression of MYB and MYC mRNA in AML	[112]
		ALKBH5	N.A.	Approximately 10.5% of AML patients carry CNVs of ALKBH5, which predicts poor prognosis and p53 mutations	[113]
	Gastric cancer	METTL3	HDGF	METTL3 causes m⁶A to accumulate on HDGF mRNA, which indicates proliferation and poor prognosis of gastric cancer	[114]
			ZMYM1	METTL3 enhances the stability of ZMYM1 mRNA to accelerate EMT and metastasis	[115]
			SEC62	METTL3 reduces m⁶A on SEC62 with the help with MiR-4429	[116]
	Hepatic carcinoma	METTL3	SOCS2	METTL3 works with YTHDF2 together to enhance the degradation of SOCS2 m⁶A-containing mRNA, which leads to HCC	[117]
		YTHDF2	EGFR	YTHDF2 suppresses ERK/MAPK signalling cascades and cell proliferation via destabilizing the EGFR mRNA	[118]
		METTL14	N.A.	The expression of METTL14 is decreased in HCC, especially in metastatic HCC	[119]
	Pancreatic cancer	METTL3	N.A.	METTL3 protein, m⁶A abundance and mRNA levels are much higher in tumour specimens than in para-cancerous specimens	[120]
		YTHDF2	YAP	Increased YTHDF2 promotes proliferation and suppresses migration of pancreatic cancer by destabilizing YAP mRNA	[121]
	Lung cancer	METTL3	EGFR/ TAZ	METTL3 enhances the translation of EGFR and TAZ mRNA in lung cancer	[56]
		SUMOylated METTL3	N.A.	SUMOylated METTL3 promotes NSCLC by diminishing the amount of m⁶A	[122]
		YTHDF2	6PGD	YTHDF2 enhances 6PGD mRNA translation by binding to m⁶A sites uniquely in lung cancer cells	[123]
		FTO	USP7	FTO stabilizes and increases the expression of USP7 by reducing m⁶A content	[124]
		FTO	MZF1	Overexpressed FTO accelerates oncogene MZF1 expression by diminishing m6A and stabilizing MZF1 in LUSC	[125, 126]
	Glioblastoma	METTL3/ METTL14	ADAM19	Decreased METTL3 or METTL14 determines the diminution of m⁶A on ADAM19 mRNA, which promotes the expression of protein and contributes to glioblastoma	[127, 128]
	Glioblastoma	ALKBH5	FOXM1	Increased levels of ALKBH5 lead to decreased levels of m⁶A on FOXM1 mRNA and enhance protein translation, which predicts poor prognosis	[129, 130]
		METTL3	SOX2	Elevated METTL3 stabilizes SOX2 mRNA and enhances radio-resistance of glioblastoma	[131]
	Prostate cancer	YTHDF2	N.A.	Downregulated YTHDF2 suppresses the proliferation and migration of prostate cancer by elevating m⁶A contents	[132]
	Bladder cancer	METTL3	PTEN	With the help of pri-miR221/222, upregulated METTL3 leads to downregulated PTEN and tumorigenesis of cancer	[133]
	Breast cancer	ALKBH5	KLF4/ NANOG	m⁶A on KLF4 and NANOG can be suppressed by the cooperation of ZNF17 and ALKBH5 to promote protein expression and contribute to breast cancer	[134, 135]
	Breast cancer	METTL3	HBXIP	Enhanced levels of m⁶A on HBXIP are attributed to increased METTL3 and promote the proliferation of breast cancer stem cells	[136]
		FTO	BNIP3	Elevated FTO leads to decreased expression of BNIP3 and metastasis of breast cancer	[137]
	Cervical cancer	FTO	β-catenin	High expression of FTO and low levels of β-catenin lead to chemoradiotherapy resistance in cervical squamous cell carcinoma	[138]
	Endometrial cancer	METTL14/METTL3	N.A.	Either mutated METTL14 or reduced METTL3 activates the AKT signalling pathway and stimulates proliferation and tumorigenicity by limiting the expression of m⁶A	[139]
	Ocular melanoma	YTHDF1	HINT2	YTHDF1 promotes the translation of methylated HINT2 mRNA and inhibits the progression of ocular melanoma	[140]
m¹A	Ovarian/Breast cancer	ALKBH3	CSF-1	Accumulated ALKBH3 indicates improved CSF-1 mRNA expression and invasion of cancer cells	[141]
	Gastrointestinal cancer	ALKBH3	ErbB2/ AKT1S1	Aberrant m¹A modifications regulate gastrointestinal cancer by modulating the mTOR pathway associated with cell proliferation	[142]
	Urothelial carcinoma	ALKBH3	N.A.	ALKBH3 promotes the progression, angiogenesis and invasion of urothelial carcinomas via NOX-2-ROS and TWEAK/Fn14-VEGF signals	[143]
m⁵C	Skin cancer	NSUN2	N.A.	Inactivating NSUN2 prevents protein translation and stimulates the tumour-initiating population of skin cancer	[144]
	Breast cancer	NSUN2	N.A.	NSUN2 is reported to be upregulated at the mRNA and protein levels	[145]
	Urothelial carcinoma	YBX1	HDGF	m⁵C modified 3'UTR in HDGF mRNA can be recognized by YBX1 and activate the advancement of UCB	[78]
	Lung cancer	N.A.	N.A.	M⁵C RNA modification is upregulated in circulating tumour cells from patients with lung cancer	[146]
Ψ	Prostate cancer	DKC1	N.A.	Certain nucleolar RNAs (H/ACA snoRNAs) and DKC1 that transfer U to Ψ contribute to the progression of cancer	[147]
Ψ	Haematological malignancies	N.A.	N.A.	H/ACA snoRNAs are limited in acute leukaemia, lymphoma and multiple myeloma	[150‐152]
I	Hepatocellular carcinoma	ADAR1	AZIN1	Edited AZIN1 stimulates S/G conversion and induces proliferation and poor prognosis in hepatocellular carcinoma	[153, 154]
		ADAR1	BLCAP	Increased editing of BLCAP accelerates cell proliferation by activating the Akt/mTOR signalling pathway or STAT3	[158]
	Cervical cancer	ADAR1	BLCAP	Increased editing of BLCAP accelerates cell proliferation by activating the Akt/mTOR signalling pathway or STAT3	[157]
	Breast cancer	ADAR1	DHFR	Editing of DHFR by ADAR1 stabilizes mRNA and accelerates cell growth	[159]
	Gastric cancer	ADAR2	PODXL	Downregulated ADAR2 reduces the decoration on PODXL and increases the malignancy of gastric cancer	[160]
	Lung adenocarcinoma	ADARB1	N.A.	ADARB1 has low expression in H358 and A549 lung adenocarcinoma cells	[161]
U	Thyroid carcinoma	UPP1	N.A.	It is reported that the expression of UPP1 significantly depends on lymph node metastasis, tumour stage and size	[164]

Clinical prospects of RNA modifications

RNA modifications and enzyme complexes exhibit upregulated and downregulated levels of expression in cancers, which means RNA modifications can serve as biomarkers to diagnose diseases in a manner that is helpful and precise. For example, upregulated YTHDF2 is found in pancreatic cancer, increased m⁵C is detected in lung cancer and accumulated Ψ contributes to the advancement of prostate cancer [121, 146, 147]. However, other biomarkers need to be elucidated. Besides biomarkers to diagnose cancers, RNA modifications are also biomarkers to predict patient prognosis. Since they stimulate or inhibit the progression of cancer, RNA modifications have therapeutic potential. 3-deazaadenosine (DAA) interrupts METTL3/14 and inhibits the decoration of m⁶A by obstructing SAH hydrolase [165], SPI1 is considered a potential target for AML because of inhibition of METTL14 [112], and meclofenamic acid (MA), a non-steroidal anti-inflammatory drug, silences FTO by competing for binding sites [166]. Novel targets for treatment of cancer require further investigation.

Conclusion

In summary, chemical modifications in mRNA are vital for many processes of cell life, such as pre-mRNA splicing, nuclear export, transcript stability and translation initiation. Importantly, RNA modifications play a critical role in driving cell fate in cancer. The importance of the relationship between RNA modification and various diseases cannot be overly emphasized. In this review, we redefined the bridge between transcription and translation and applied it to physiological and pathological processes. To date, we have demonstrated 2 roles of mRNA modifications in transcription. Generally, one type is mRNA modifications that can change the structure of transcripts, and the other is mRNA modifications that can regulate transcription by joining hands with a complex of enzymes, such as METTL3 or NSUN2. Considering that modifications can regulate the fate of diverse diseases, such modifications have the potential to be utilized in targeted therapy. Surely, RNA modifications as well as the related diseases mentioned above are a fraction of those affecting human beings in nature. Thus, these modifications need to be elucidated in the following few years.

Acknowledgements

Not applicable

Competing interests

The authors declare that they have no competing interests.

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Titel: Novel insight into the regulatory roles of diverse RNA modifications: Re-defining the bridge between transcription and translation
verfasst von: Hanhan Shi
Peiwei Chai
Renbing Jia
Xianqun Fan
Publikationsdatum: 01.12.2020
Verlag: BioMed Central
Erschienen in: Molecular Cancer / Ausgabe 1/2020
Elektronische ISSN: 1476-4598
DOI: https://doi.org/10.1186/s12943-020-01194-6

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Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

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

Abstract

Publisher’s Note

Introduction

The regulatory role of RNA modifications

m⁶A RNA modification

Introduction to m⁶A RNA modification

Regulatory role of m⁶A RNA modification in molecular functions

m¹A RNA modification

Introduction of m¹A RNA modification

Regulatory role of the m¹A RNA modification in molecular functions

m⁵C RNA modification

Introduction of the m⁵C RNA modification

Regulatory role of the m⁵C RNA modification in molecular functions

Other RNA modifications

hm⁵C

Ψ

I and U

2’-O-Me

Regulatory roles of RNA modifications in pathogenesis

Aberrant m⁶A RNA modifications in diseases

Aberrant m¹A RNA modification in diseases

Aberrant m⁵C RNA modification in diseases

Aberrant hm⁵C, Ψ, I, U and 2’-O-Me RNA modifications in diseases

Clinical prospects of RNA modifications

Conclusion

Acknowledgements

Competing interests

Publisher’s Note

Neu im Fachgebiet Onkologie

„Überwältigende“ Evidenz für Tripeltherapie beim metastasierten Prostata-Ca.

So sicher sind Tattoos: Neue Daten zur Risikobewertung

CAR-M-Zellen: Warten auf das große Fressen

Blutdrucksenkung könnte Uterusmyome verhindern

Update Onkologie

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Abstract

Publisher’s Note

Introduction

The regulatory role of RNA modifications

m6A RNA modification

Introduction to m6A RNA modification

Regulatory role of m6A RNA modification in molecular functions

m1A RNA modification

Introduction of m1A RNA modification

Regulatory role of the m1A RNA modification in molecular functions

m5C RNA modification

Introduction of the m5C RNA modification

Regulatory role of the m5C RNA modification in molecular functions

Other RNA modifications

hm5C

Ψ

I and U

2’-O-Me

Regulatory roles of RNA modifications in pathogenesis

Aberrant m6A RNA modifications in diseases

Aberrant m1A RNA modification in diseases

Aberrant m5C RNA modification in diseases

Aberrant hm5C, Ψ, I, U and 2’-O-Me RNA modifications in diseases

Clinical prospects of RNA modifications

Conclusion

Acknowledgements

Ethics approval and consent to participate

Consent for publication

Competing interests

Publisher’s Note

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Update Onkologie

m⁶A RNA modification

Introduction to m⁶A RNA modification

Regulatory role of m⁶A RNA modification in molecular functions

m¹A RNA modification

Introduction of m¹A RNA modification

Regulatory role of the m¹A RNA modification in molecular functions

m⁵C RNA modification

Introduction of the m⁵C RNA modification

Regulatory role of the m⁵C RNA modification in molecular functions

hm⁵C

Aberrant m⁶A RNA modifications in diseases

Aberrant m¹A RNA modification in diseases

Aberrant m⁵C RNA modification in diseases

Aberrant hm⁵C, Ψ, I, U and 2’-O-Me RNA modifications in diseases