A Vastly Increased Chemical Variety of RNA Modifications Containing a Thioacetal Structure

Magro, Christina Dal; Keller, Patrick; Kötter, Annika; Werner, Stephan; Duarte, Victor; Marchand, Virginie; Ignarski, Michael; Freiwald, Anja; Müller, Roman‐Ulrich; Dieterich, Christoph; Motorin, Yuri; Butter, Falk; Atta, Mohamed; Helm, Mark

doi:10.1002/anie.201713188

Cited by 45 publications

(68 citation statements)

References 24 publications

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“…Dependent on organism and RNA species, modifications vary in their frequency, being crucial for functionality of highly abundant and extensively modified tRNA [6] or major players in mRNA-associated regulation of gene expression [7]. Additionally, a wide range of alterations, from single methylations on adenosine as in m 1 A or m 6 A, up to complex modifications comprising multiple steps of formation and rare biological structures such as a thioacetal [8] has been identified. From this variety, several modifications are considered key factors in cancer research, hence emphasizing the importance of m 1 A, m 6 A, m 5 C, inosine and pseudouridine [9].…”

Section: Introductionmentioning

confidence: 99%

Manganese Ions Individually Alter the Reverse Transcription Signature of Modified Ribonucleosides

Kristen

Plehn

Marchand

et al. 2020

Genes

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Reverse transcription of RNA templates containing modified ribonucleosides transfers modification-related information as misincorporations, arrest or nucleotide skipping events to the newly synthesized cDNA strand. The frequency and proportion of these events, merged from all sequenced cDNAs, yield a so-called RT signature, characteristic for the respective RNA modification and reverse transcriptase (RT). While known for DNA polymerases in so-called error-prone PCR, testing of four different RTs by replacing Mg2+ with Mn2+ in reaction buffer revealed the immense influence of manganese chloride on derived RT signatures, with arrest rates on m1A positions dropping from 82% down to 24%. Additionally, we observed a vast increase in nucleotide skipping events, with single positions rising from 4% to 49%, thus implying an enhanced read-through capability as an effect of Mn2+ on the reverse transcriptase, by promoting nucleotide skipping over synthesis abortion. While modifications such as m1A, m22G, m1G and m3C showed a clear influence of manganese ions on their RT signature, this effect was individual to the polymerase used. In summary, the results imply a supporting effect of Mn2+ on reverse transcription, thus overcoming blockades in the Watson-Crick face of modified ribonucleosides and improving both read-through rate and signal intensity in RT signature analysis.

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Section: Introductionmentioning

confidence: 99%

Manganese Ions Individually Alter the Reverse Transcription Signature of Modified Ribonucleosides

Kristen

Plehn

Marchand

et al. 2020

Genes

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“…Over 170 different RNA modifications are known to decorate RNA molecules [24]. In the last few years, a vast amount of efforts have been devoted to functionally dissecting the biological role of N6-methyladenosine (m 6 A), the most prevalent internal RNA modification found in human mRNAs.…”

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confidence: 99%

Integrative analyses of the RNA modification machinery reveal tissue- and cancer-specific signatures

et al. 2020

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Background: RNA modifications play central roles in cellular fate and differentiation. However, the machinery responsible for placing, removing, and recognizing more than 170 RNA modifications remains largely uncharacterized and poorly annotated, and we currently lack integrative studies that identify which RNA modificationrelated proteins (RMPs) may be dysregulated in each cancer type. Results: Here, we perform a comprehensive annotation and evolutionary analysis of human RMPs, as well as an integrative analysis of their expression patterns across 32 tissues, 10 species, and 13,358 paired tumor-normal human samples. Our analysis reveals an unanticipated heterogeneity of RMP expression patterns across mammalian tissues, with a vast proportion of duplicated enzymes displaying testisspecific expression, suggesting a key role for RNA modifications in sperm formation and possibly intergenerational inheritance. We uncover many RMPs that are dysregulated in various types of cancer, and whose expression levels are predictive of cancer progression. Surprisingly, we find that several commonly studied RNA modification enzymes such as METTL3 or FTO are not significantly upregulated in most cancer types, whereas several less-characterized RMPs, such as LAGE3 and HENMT1, are dysregulated in many cancers. Conclusions: Our analyses reveal an unanticipated heterogeneity in the expression patterns of RMPs across mammalian tissues and uncover a large proportion of dysregulated RMPs in multiple cancer types. We provide novel targets for future cancer research studies targeting the human epitranscriptome, as well as foundations to understand cell type-specific behaviors that are orchestrated by RNA modifications.

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“…An explanation of the reaction mechanism has been proposed in which the transfer of a methyl group from another molecule of SAM to the sulfur atom of the tip of the polysulfide attached to the Aux cluster is followed by attack of a substrate radical on the methylated sulfur atom to generate ms 2 A ( Landgraf et al, 2013 ; Figure 2E ). Recently, a hypermodified nucleoside, 2-methylthiomethylenethio-A (msms 2 A), was identified in E. coli tRNAs, and MiaB is involved in msms 2 A synthesis ( Dal Magro et al, 2018 ). MiaB may abstract a hydrogen radical from the methyl group of ms 2 A, which is introduced in the first step of the reaction, and a second methylthio transfer reaction could then follow.…”

Section: The Role Of Radical S -Adenosylmethioninementioning

confidence: 99%

Recent Advances in Our Understanding of the Biosynthesis of Sulfur Modifications in tRNAs

Shigi

2018

Front. Microbiol.

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Sulfur is an essential element in all living organisms. In tRNA molecules, there are many sulfur-containing nucleosides, introduced post-transcriptionally, that function to ensure proper codon recognition or stabilization of tRNA structure, thereby enabling accurate and efficient translation. The biosynthesis of tRNA sulfur modifications involves unique sulfur trafficking systems that are closely related to cellular sulfur metabolism, and “modification enzymes” that incorporate sulfur atoms into tRNA. Herein, recent biochemical and structural characterization of the biosynthesis of sulfur modifications in tRNA is reviewed, with special emphasis on the reaction mechanisms of modification enzymes. It was recently revealed that TtuA/Ncs6-type 2-thiouridylases from thermophilic bacteria/archaea/eukaryotes are oxygen-sensitive iron-sulfur proteins that utilize a quite different mechanism from other 2-thiouridylase subtypes lacking iron-sulfur clusters such as bacterial MnmA. The various reaction mechanisms of RNA sulfurtransferases are also discussed, including tRNA methylthiotransferase MiaB (a radical S-adenosylmethionine-type iron-sulfur enzyme) and other sulfurtransferases involved in both primary and secondary sulfur-containing metabolites.

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A Vastly Increased Chemical Variety of RNA Modifications Containing a Thioacetal Structure

Cited by 45 publications

References 24 publications

Manganese Ions Individually Alter the Reverse Transcription Signature of Modified Ribonucleosides

Manganese Ions Individually Alter the Reverse Transcription Signature of Modified Ribonucleosides

Integrative analyses of the RNA modification machinery reveal tissue- and cancer-specific signatures

Recent Advances in Our Understanding of the Biosynthesis of Sulfur Modifications in tRNAs

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