Modified nucleotides may have enhanced early RNA catalysis

Wolk, Steven K.; Mayfield, Wesley S.; Gelinas, Amy D.; Astling, David P.; Guillot, J. C.; Brody, Edward N.; Janjić, Nebojša; Gold, Larry

doi:10.1073/pnas.1809041117

Cited by 18 publications

(13 citation statements)

References 62 publications

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“…New, engineered polymerases are not required to cope with unnatural chemistry introduced at position 5 of pyrimidines (32). Base modified nucleotides have also been proposed as elements in an RNA world to promote the catalytic activity of RNA-based catalysts (33). Alternatively, click chemistry with alkyne-modified nucleotides can be used to select for nucleobase-modified aptamers (34).…”

Section: Significancementioning

confidence: 99%

Evolution of abiotic cubane chemistries in a nucleic acid aptamer allows selective recognition of a malaria biomarker

Cheung

Röthlisberger

Mechaly

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Nucleic acid aptamers selected through systematic evolution of ligands by exponential enrichment (SELEX) fold into exquisite globular structures in complex with protein targets with diverse translational applications. Varying the chemistry of nucleotides allows evolution of nonnatural nucleic acids, but the extent to which exotic chemistries can be integrated into a SELEX selection to evolve nonnatural macromolecular binding interfaces is unclear. Here, we report the identification of a cubane-modified aptamer (cubamer) against the malaria biomarker Plasmodium vivax lactate dehydrogenase (PvLDH). The crystal structure of the complex reveals an unprecedented binding mechanism involving a multicubane cluster within a hydrophobic pocket. The binding interaction is further stabilized through hydrogen bonding via cubyl hydrogens, previously unobserved in macromolecular binding interfaces. This binding mechanism allows discriminatory recognition of P. vivax over Plasmodium falciparum lactate dehydrogenase, thereby distinguishing these highly conserved malaria biomarkers for diagnostic applications. Together, our data demonstrate that SELEX can be used to evolve exotic nucleic acids bearing chemical functional groups which enable remarkable binding mechanisms which have never been observed in biology. Extending to other exotic chemistries will open a myriad of possibilities for functional nucleic acids.

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Section: Significancementioning

confidence: 99%

Evolution of abiotic cubane chemistries in a nucleic acid aptamer allows selective recognition of a malaria biomarker

Cheung

Röthlisberger

Mechaly

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…An alternative would be that just one of the two changed, with the other motif order occurring subsequently via a true circular permutation event ( 38 , 41 ) (not shown). Presumably, the ancestral MTase(s) as described here would methylate free adenine or a free adenine nucleotide, perhaps contributing to pre-protein metabolism ( 42 , 43 ).…”

Section: Introductionmentioning

confidence: 99%

Beta class amino methyltransferases from bacteria to humans: evolution and structural consequences

Woodcock

Horton

Zhang

et al. 2020

Nucleic Acids Research

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S-adenosyl-l-methionine dependent methyltransferases catalyze methyl transfers onto a wide variety of target molecules, including DNA and RNA. We discuss a family of methyltransferases, those that act on the amino groups of adenine or cytosine in DNA, have conserved motifs in a particular order in their amino acid sequence, and are referred to as class beta MTases. Members of this class include M.EcoGII and M.EcoP15I from Escherichia coli, Caulobacter crescentus cell cycle–regulated DNA methyltransferase (CcrM), the MTA1-MTA9 complex from the ciliate Oxytricha, and the mammalian MettL3-MettL14 complex. These methyltransferases all generate N6-methyladenine in DNA, with some members having activity on single-stranded DNA as well as RNA. The beta class of methyltransferases has a unique multimeric feature, forming either homo- or hetero-dimers, allowing the enzyme to use division of labor between two subunits in terms of substrate recognition and methylation. We suggest that M.EcoGII may represent an ancestral form of these enzymes, as its activity is independent of the nucleic acid type (RNA or DNA), its strandedness (single or double), and its sequence (aside from the target adenine).

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“…451,471,518 The realisation that nucleic acid scaffolds required substantial concentrations of M 2+ cofactors for activity to compensate the dearth of functional groups present on the nucleobases and backbone, combined with the notorious fragility to nucleases, rapidly called for the introduction of modified nucleotides in SELEX experiments. 533 and have permitted (and will certainly continue) expansion of the catalytic repertoire of DNAzymes and ribozymes.…”

Section: Modified Catalytic Nucleic Acid Enzymesmentioning

confidence: 99%