Structure and Function of Noncanonical Nucleobases

Carell, Thomas; Brandmayr, Caterina; Hienzsch, Antje; Müller, Markus; Pearson, David; Reiter, Veronika; Thoma, Ines; Thumbs, Peter; Wagner, Mirko

doi:10.1002/anie.201201193

Cited by 175 publications

(153 citation statements)

References 259 publications

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“…Owing to essential activities in protein synthesis and newly discovered functions in gene regulation, RNA is uniquely positioned in such a network to accurately capture the overall behavior of biological systems, as well as the specific metabolic and epigenetic state of a cell. The RNA building blocks display numerous variations of the four canonical bases, which contribute to defining the breathtaking diversity of structures and functions characteristic of natural RNA (Chang and Varani 1997;Carell et al 2012). These post-transcriptional modifications (PTMs) are introduced by the activity of specialized enzymes that, in many cases, have been identified and investigated (Ferré-D'Amaré 2003).…”

Section: Introductionmentioning

confidence: 99%

Profiling ribonucleotide modifications at full-transcriptome level: a step toward MS-based epitranscriptomics

Rose

Quinn

Sayre

et al. 2015

RNA

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The elucidation of the biological significance of RNA post-transcriptional modifications is hampered by the dearth of effective high-throughput sequencing approaches for detecting, locating, and tracking their levels as a function of predetermined experimental factors. With the goal of confronting this knowledge gap, we devised a strategy for completing global surveys of all ribonucleotide modifications in a cell, which is based on the analysis of whole cell extracts by direct infusion electrospray ionization mass spectrometry (ESI-MS). Our approach eschews chromatographic separation to promote instead the direct application of MS techniques capable of providing detection, differentiation, and quantification of post-transcriptional modifications (PTMs) in complex ribonucleotide mixtures. Accurate mass analysis was used to carry out database-aided identification of PTMs, whereas multistep tandem mass spectrometry (MS n ) and consecutive reaction monitoring (CRM) provided the necessary structural corroboration. We demonstrated that heat-map plots afforded by ion mobility spectrometry mass spectrometry (IMS-MS) can provide comprehensive modification profiles that are unique for different cell types and metabolic states. We showed that isolated tRNA samples can be used as controlled sources of PTMs in standard-additions quantification. Intrinsic internal standards enable direct comparisons of heat-maps obtained under different experimental conditions, thus offering the opportunity to evaluate the global effects of such conditions on the expression levels of all PTMs simultaneously. This type of comparative analysis will be expected to support the investigation of the system biology of RNA modifications, which will be aimed at exploring mutual correlations of their expression levels and providing new valuable insights into their biological significance.

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Section: Introductionmentioning

confidence: 99%

Profiling ribonucleotide modifications at full-transcriptome level: a step toward MS-based epitranscriptomics

Rose

Quinn

Sayre

et al. 2015

RNA

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“…tRNA splicing endonucleases are localized on yeast mitochondria (Yoshihisa et al 2003), and human tRNA isopentenyl transferase has a possible mitochondrial targeting signal (Golovko et al 2000). Several modification reactions occur while tRNA is in a precursor form (Carell et al 2012); thus it is conceivable that membrane affinity anchors isopentenylated pre-tRNA Sec to the mitochondrial outer surface during splicing. Indeed, transient or permanent membrane residence might stimulate any RNA process with a slow or rare membrane phase.…”

Section: Modified Cellular Human Trnamentioning

confidence: 99%

Human tRNA^Secassociates with HeLa membranes, cell lipid liposomes, and synthetic lipid bilayers

Janas

Yarus

2012

RNA

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We have shown previously that simple RNA structures bind pure phospholipid liposomes. However, binding of bona fide cellular RNAs under physiological ionic conditions is shown here for the first time. Human tRNA Sec contains a hydrophobic anticodon-loop modification: N 6 -isopentenyladenosine (i 6 A) adjacent to its anticodon. Using a highly specific double-probe hybridization assay, we show mature human tRNA Sec specifically retained in HeLa intermediate-density membranes. Further, isolated human tRNA Sec rebinds to liposomes from isolated HeLa membrane lipids, to a much greater extent than an unmodified tRNA Sec transcript. To better define this affinity, experiments with pure lipids show that liposomes forming rafts or including positively charged sphingosine, or particularly both together, exhibit increased tRNA Sec binding. Thus tRNA Sec residence on membranes is determined by several factors, such as hydrophobic modification (likely isopentenylation of tRNA Sec ), lipid structure (particularly lipid rafts), or sphingosine at a physiological concentration in rafted membranes. From prior work, RNA structure and ionic conditions also appear important. tRNA Sec dissociation from HeLa liposomes implies a mean membrane residence of 7.6 min at 24°C (t 1 ⁄ 2 = 5.3 min). Clearly RNA with a 5-carbon hydrophobic modification binds HeLa membranes, probably favoring raft domains containing specific lipids, for times sufficient to alter biological fates.

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“…We begin this journey by illustrating the widespread occurrence of modified bases in the biological world. [1] …”

Section: Introductionmentioning

confidence: 99%

On the Origin of the Canonical Nucleobases: An Assessment of Selection Pressures across Chemical and Early Biological Evolution

Rios

Tor

2013

Israel Journal of Chemistry

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The native bases of RNA and DNA are prominent examples of the narrow selection of organic molecules upon which life is based. How did nature “decide” upon these specific heterocycles? Evidence suggests that many types of heterocycles could have been present on the early Earth. It is therefore likely that the contemporary composition of nucleobases is a result of multiple selection pressures that operated during early chemical and biological evolution. The persistence of the fittest heterocycles in the prebiotic environment towards, for example, hydrolytic and photochemical assaults, may have given some nucleobases a selective advantage for incorporation into the first informational polymers. The prebiotic formation of polymeric nucleic acids employing the native bases remains, however, a challenging problem to reconcile. Hypotheses have proposed that the emerging RNA world may have included many types of nucleobases. This is supported by the extensive utilization of non-canonical nucleobases in extant RNA and the resemblance of many of the modified bases to heterocycles generated in simulated prebiotic chemistry experiments. Selection pressures in the RNA world could have therefore narrowed the composition of the nucleic acid bases. Two such selection pressures may have been related to genetic fidelity and duplex stability. Considering these possible selection criteria, the native bases along with other related heterocycles seem to exhibit a certain level of fitness. We end by discussing the strength of the N-glycosidic bond as a potential fitness parameter in the early DNA world, which may have played a part in the refinement of the alphabetic bases.

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Structure and Function of Noncanonical Nucleobases

Cited by 175 publications

References 259 publications

Profiling ribonucleotide modifications at full-transcriptome level: a step toward MS-based epitranscriptomics

Profiling ribonucleotide modifications at full-transcriptome level: a step toward MS-based epitranscriptomics

Human tRNA^Secassociates with HeLa membranes, cell lipid liposomes, and synthetic lipid bilayers

On the Origin of the Canonical Nucleobases: An Assessment of Selection Pressures across Chemical and Early Biological Evolution

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Structure and Function of Noncanonical Nucleobases

Cited by 175 publications

References 259 publications

Profiling ribonucleotide modifications at full-transcriptome level: a step toward MS-based epitranscriptomics

Profiling ribonucleotide modifications at full-transcriptome level: a step toward MS-based epitranscriptomics

Human tRNASecassociates with HeLa membranes, cell lipid liposomes, and synthetic lipid bilayers

On the Origin of the Canonical Nucleobases: An Assessment of Selection Pressures across Chemical and Early Biological Evolution

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Human tRNA^Secassociates with HeLa membranes, cell lipid liposomes, and synthetic lipid bilayers