RNA 2′-O-Methylation (Nm) Modification in Human Diseases

Dimitrova, Dilyana G; Teysset, Laure; Carré, Clément

doi:10.3390/genes10020117

Cited by 154 publications

(158 citation statements)

References 217 publications

(257 reference statements)

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“…These mRNA cap modifications have been shown to have a wide variety of functions. For example, the m 7 G modification in the mRNA cap recruits the translation initiation machinery for cap-dependent translation, and Cap 1 2’O methylation can further enhance this translation (8, 10, 11). mRNA cap 2’O methylation has also been shown to prevent degradation of modified transcripts by exoribonucleases or serve as a motif that marks mRNA as “self” to prevent recognition by the IFN-induced RNA binding proteins RIG-I and IFIT1 (12-15).…”

Section: Introductionmentioning

confidence: 99%

The mRNA cap 2’O methyltransferase CMTR1 regulates the expression of certain interferon-stimulated genes

Williams

Gokhale

Snider

et al. 2020

Preprint

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AbstractType I interferons (IFN) initiate an antiviral state through a signal transduction cascade that leads to the induction of hundreds of IFN-stimulated genes (ISGs) to restrict viral infection. Recently, RNA modifications on both host and viral RNAs have been described as regulators of infection. However, the impact of host mRNA cap modifications on the IFN response and how this regulates viral infection is unknown. Here, we reveal that CMTR1, an ISG that catalyzes 2’O methylation of the first transcribed nucleotide in cellular mRNA (Cap 1), promotes the protein expression of specific ISGs that contribute to the antiviral response. Depletion of CMTR1 reduces the IFN-induced protein levels of ISG15, MX1, and IFITM1, without affecting their transcript abundance. However, CMTR1 depletion does not significantly affect the IFN-induced protein or transcript abundance of IFIT1 and IFIT3. Importantly, knockdown of IFIT1, which acts with IFIT3 to inhibit the translation of RNAs lacking Cap 1 2’O methylation, restores protein expression of ISG15, MX1, and IFITM1 in cells depleted of CMTR1. Finally, we found that CMTR1 plays a role in restricting RNA virus replication, likely by ensuring the expression of specific antiviral ISGs. Taken together, these data reveal that CMTR1 is required to establish an antiviral state by ensuring the protein expression of a subset of ISGs during the type I IFN response.ImportanceInduction of an efficient type I IFN response is important to control viral infection. We show that the host 2’O methyltransferase CMTR1 facilitates the protein expression of ISGs in human cells by preventing IFIT1 from inhibiting the translation of these mRNAs lacking cap 2’O methylation. Thus, CMTR1 promotes the IFN-mediated antiviral response.

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Section: Introductionmentioning

confidence: 99%

The mRNA cap 2’O methyltransferase CMTR1 regulates the expression of certain interferon-stimulated genes

Williams

Gokhale

Snider

et al. 2020

Preprint

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“…2'-O-methylation (Nm) is a common RNA modification. The addition of a methyl group to the 2' hydroxyl of the ribose moiety of a nucleoside creates Nm (reviewed in (4,5) ). Nm can occur at any nucleotide explaining the abundant nature of this modification.…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have uncovered crucial roles for FTSJ1/TRM7 in normal and pathological conditions (reviewed in (4,5) ). While in S. cerevisiae , lack of TRM7 affected growth, FTSJ1 mutant mice showed impairment in their learning capacity as well as significantly reduced pain sensing (hypoalgesia) and altered gene expression profiles (40) .…”

Section: Introductionmentioning

confidence: 99%

tRNA 2’-O-methylation modulates small RNA silencing and life span in Drosophila

Angelova

Dimitrova

Silva

et al. 2019

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2'-O-methylation (Nm) represents one of the most common RNA modifications. Nm affects RNA structure and function with crucial roles in various RNA-mediated processes ranging from RNA silencing, translation, self versus non-self recognition to viral defense mechanisms. Here, we identify two novel Nm methyltransferases (Nm-MTases) in Drosophila melanogaster (CG7009 and CG5220) as functional orthologs of yeast TRM7 and human FTSJ1, respectively. Genetic knockout studies together with MALDI-TOF mass spectrometry and RiboMethSeq mapping revealed that CG7009 is responsible for methylating the wobble position in tRNA Phe , tRNA Trp and tRNA Leu , while subsequently, CG5220 methylates position C32 in the same tRNAs and targets also additional tRNAs. CG7009 or CG5220 mutant animals were viable and fertile but exhibited various phenotypes such as life span reduction, small RNA pathways dysfunction and increased sensitivity to RNA virus infections. Our results provide the first detailed characterization of two TRM7 family members in Drosophila and uncover a molecular link between enzymes catalysing Nm at specific tRNAs and small RNA-induced gene silencing pathways.

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“…Indeed, they play a crucial role throughout all tRNA biogenesis steps, such as sequence maturation, folding, recycling and degradation. Interestingly, there is a crosstalk between the different modification pathways and a large amount of tRNA modification enzymes defects have been linked to human pathologies (Angelova et al, 2018;Sokołowski et al, 2018;Dimitrova et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…It is found in tRNAs, rRNAs, snRNAs (small nuclear RNAs) at the 3' end of some small non-coding RNAs (such as piRNAs) and at some sites on mRNAs (Jordan Ontiveros et al, 2019). This modification plays a wide range of roles in RNA structure, stability and interactions (Dimitrova et al, 2019). It has been recently shown that Drosophila proteins CG7009 and CG5220 are the functional orthologues of yeast TRM7 (Pintard et al, 2002) and human FTSJ1 (Guy et al, 2015) respectively, which are involved in 2'-O-methylation of the anticodon loop of several conserved tRNAs substrates (tRNA-Leu, Trp, Phe) in different species, including Drosophila.…”

Section: Introductionmentioning

confidence: 99%

tRNA fragments (tRFs) populations analysis in mutants affecting tRNAs processing and tRNA methylation

Mollà-Herman¹,

Angelova²,

Carré³

et al. 2019

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tRNA fragments (tRFs) are a class of small non-coding RNAs (sncRNAs) derived from tRNAs. tRFs are highly abundant in many cell types including stem cells and cancer cells, and are found in all domains of life. Beyond translation control, tRFs have several functions ranging from transposon silencing to cell proliferation control. However, the analysis of tRFs presents specific challenges and their biogenesis is not well understood. They are very heterogeneous and highly modified by numerous post-transcriptional modifications. Here we describe a bioinformatic pipeline to study tRFs populations and shed light onto tRNA fragments biogenesis. Indeed, we used small RNAs Illumina sequencing datasets extracted from wild type and mutant Drosophila ovaries affecting two different highly conserved steps of tRNA biogenesis: 5'pre-tRNA processing (RNase-P subunit Rpp30) and tRNA 2'-O-methylation (CG7009 and CG5220). Using our pipeline, we show how defects in tRNA biogenesis affect nuclear and mitochondrial tRFs populations and other small non-coding RNAs biogenesis, such as small nucleolar RNAs (snoRNAs). This tRF analysis workflow will advance the current understanding of tRFs biogenesis, which is crucial to better comprehend tRFs roles and their implication in human pathology. MATERIALS AND METHODS Fly stocksFly stocks are described in (Molla-Herman et al., 2015;M. Angelova, 2019). RNA extraction from ovariesRNA was extracted from Drosophila ovaries following standard methods detailed in (Molla-Herman et al., 2015;M. Angelova, 2019). Small RNA sequencingRNA samples of 3-5 µg were used for High-throughput sequencing using Illumina HiSeq, 10% single-reads lane 1×50 bp. (Fasteris). 15-29 nt RNAs sequences excluding rRNA (riboZero) were sequenced. All the analyses were performed with Galaxy tools https://mississippi.snv.jussieu.fr. Data set deposition is described in (Molla-Herman et al., 2015;M. Angelova, 2019). European Nucleotide Archive (ENA) of the EMBL-EBI (http://www.ebi.ac.uk/ena), accession numbers: PRJEB10569 (Rpp30 mutants), PRJEB35301 and PRJEB35713 (Nm mutants). Clipping and concatenationRaw data were used for clipping the adaptors [Clip adapter (Galaxy-Version 2.3.0, owner: artbio)] and FASTQ quality control was performed (FastQC Read Quality reports (Galaxy-Version 0.72)). Since replicates were homogeneous in quality and analysis (replicates for CG7009* heterozygous and homozygous, triplicates for CG7009*-CG5220* double mutants) we merged them [Concatenate multiple datasets tailto-head (Galaxy-Version 1.4.1, owner: artbio) to have single fasta files. CG7009*/Def9487 was used to obtain normalization numbers but is not shown in the figures. Data normalization using DeSeq miRNA countsData were normalized with bank Size Factors (SF) obtained by using [DESeq geometrical normalization (Galaxy-Version 1.0.1, owner: artbio)] with miRNA counts obtained using [miRcounts (Galaxy-Version 1.3.2)], allowing 0 mismatch (MM). Then, 1/SF values were used in Galaxy small RNA maps (Sup. Fig. 5). Data normalization with DeSeq using ...

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RNA 2′-O-Methylation (Nm) Modification in Human Diseases

Cited by 154 publications

References 217 publications

The mRNA cap 2’O methyltransferase CMTR1 regulates the expression of certain interferon-stimulated genes

The mRNA cap 2’O methyltransferase CMTR1 regulates the expression of certain interferon-stimulated genes

tRNA 2’-O-methylation modulates small RNA silencing and life span in Drosophila

tRNA fragments (tRFs) populations analysis in mutants affecting tRNAs processing and tRNA methylation

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