Non-enzymatic recombination of RNA: Ligation in loops

Staroseletz, Yaroslav; Nechaev, Sergey; Bichenkova, Elena V.; Bryce, Richard A.; Watson, Catherine; Vlassov, Valentin V.; Zenkova, Marina A.

doi:10.1016/j.bbagen.2017.10.019

Cited by 12 publications

(9 citation statements)

References 78 publications

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“…Previous reports of non-enzymatic RNA recombination with defined substrates suggests that the majority of such reactions are likely to involve either a concerted mechanism of direct in-line attack on an internal phosphodiester linkage or, more frequently, a two step-mechanism of two consecutive transesterification reactions via an >p intermediate generated by hydrolysis ( Lutay et al, 2007 ; Nechaev et al, 2009 ; Staroseletz et al, 2018 ). In both reaction trajectories, ligation /recombination is promoted by proximity through in trans intermolecular hybridization ( Figure 4—figure supplement 1 ) as well as the concentration and entropic effects of eutectic ice phase formation.…”

Section: Discussionmentioning

confidence: 99%

Random-sequence genetic oligomer pools display an innate potential for ligation and recombination

Mutschler

Taylor

Porebski

et al. 2018

eLife

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Recombination, the exchange of information between different genetic polymer strands, is of fundamental importance in biology for genome maintenance and genetic diversification and is mediated by dedicated recombinase enzymes. Here, we describe an innate capacity for non-enzymatic recombination (and ligation) in random-sequence genetic oligomer pools. Specifically, we examine random and semi-random eicosamer (N20) pools of RNA, DNA and the unnatural genetic polymers ANA (arabino-), HNA (hexitol-) and AtNA (altritol-nucleic acids). While DNA, ANA and HNA pools proved inert, RNA (and to a lesser extent AtNA) pools displayed diverse modes of spontaneous intermolecular recombination, connecting recombination mechanistically to the vicinal ring cis-diol configuration shared by RNA and AtNA. Thus, the chemical constitution that renders both susceptible to hydrolysis emerges as the fundamental determinant of an innate capacity for recombination, which is shown to promote a concomitant increase in compositional, informational and structural pool complexity and hence evolutionary potential.

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Section: Discussionmentioning

confidence: 99%

Random-sequence genetic oligomer pools display an innate potential for ligation and recombination

Mutschler

Taylor

Porebski

et al. 2018

eLife

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“…This might be attributed to the variations in accessibility of these two regions and/or to the different levels of their structural tension, which may affect catalysis of transesterification of the RNA phosphodiester bonds. Indeed, our recent molecular dynamics simulations (Staroseletz, Nechaev et al, 2017) showed considerable changes in the fine structure of this stem regions. Electrophoretic mobility of fragments formed upon RNA cleavage induced by the conjugates corresponded to the mobility of fragments formed by RNA cleavage with RNase T1 (Figure 2(A)) and 2 M imidazole buffer (primary data not shown), which suggests similar products formed upon cleavage with POCs and RNase T1.…”

Section: Conjugate Ribonuclease Activitymentioning

confidence: 94%

RNA knockdown by synthetic peptidyl-oligonucleotide ribonucleases: behavior of recognition and cleavage elements under physiological conditions

Gebrezgiabher

Zalloum

Clarke

et al. 2020

Journal of Biomolecular Structure and Dynamics

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Sequence-specific protein-based ribonucleases are not found in nature. Absolute sequence selectivity in RNA cleavage in vivo normally requires multi-component complexes that recruit a guide RNA or DNA for target recognition and a protein-RNA assembly for catalytic functioning (e.g. RNAi molecular machinery, RNase H). Recently discovered peptidyl-oligonucleotide synthetic ribonucleases selectively knock down pathogenic RNAs by irreversible cleavage to offer unprecedented opportunities for control of disease-relevant RNA. Understanding how to increase their potency, selectivity and catalytic turnover will open the translational pathway to successful therapeutics. Yet, very little is known about how these chemical ribonucleases bind, cleave and leave their target. Rational design awaits this understanding in order to control therapy, particularly how to overcome the trade-off between sequence specificity and potency through catalytic turnover. We illuminate this here by characterizing the interactions of these chemical RNases with both complementary and non-complementary RNAs using T m profiles, fluorescence, UV-visible and NMR spectroscopies. Crucially, the level of counter cations, which are tightly-controlled within cellular compartments, also controlled these interactions. The oligonucleotide component dominated interaction between conjugates and complementary targets in the presence of physiological levels of counter cations (K þ), sufficient to prevent repulsion between the complementary nucleic acid strands to allow Watson-Crick hydrogen bonding. In contrast, the positively-charged catalytic peptide interacted poorly with target RNA, when counter cations similarly screened the negatively-charged sugar-phosphate RNA backbones. The peptide only became the key player, when counter cations were insufficient for charge screening; moreover, only under such nonphysiological conditions did conjugates form strong complexes with non-complementary RNAs.

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“…Other mechanisms of RNA recombination have been proposed to explain the recovery of complete viral genomes from defective RNA fragments in the absence of viral RdRp. In particular, it was demonstrated that the RNA molecules are able to undergo spontaneous nonenzymatic intermolecular transesterification reactions [180,181,182,183]. This ability is linked to the predisposition of RNA to self-assembly, which enables it to form multi-motif functional complexes (ribozymes) where consecutive cleavage-ligation reactions can be performed.…”

Section: Two Main Mechanisms Of Rna Recombination In Enterovirusesmentioning

confidence: 99%

Recombination in Enteroviruses, a Multi-Step Modular Evolutionary Process

Muslin

Kain

Bessaud

et al. 2019

Viruses

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RNA recombination is a major driving force in the evolution and genetic architecture shaping of enteroviruses. In particular, intertypic recombination is implicated in the emergence of most pathogenic circulating vaccine-derived polioviruses, which have caused numerous outbreaks of paralytic poliomyelitis worldwide. Recent experimental studies that relied on recombination cellular systems mimicking natural genetic exchanges between enteroviruses provided new insights into the molecular mechanisms of enterovirus recombination and enabled to define a new model of genetic plasticity for enteroviruses. Homologous intertypic recombinant enteroviruses that were observed in nature would be the final products of a multi-step process, during which precursor nonhomologous recombinant genomes are generated through an initial inter-genomic RNA recombination event and can then evolve into a diversity of fitter homologous recombinant genomes over subsequent intra-genomic rearrangements. Moreover, these experimental studies demonstrated that the enterovirus genome could be defined as a combination of genomic modules that can be preferentially exchanged through recombination, and enabled defining the boundaries of these recombination modules. These results provided the first experimental evidence supporting the theoretical model of enterovirus modular evolution previously elaborated from phylogenetic studies of circulating enterovirus strains. This review summarizes our current knowledge regarding the mechanisms of recombination in enteroviruses and presents a new evolutionary process that may apply to other RNA viruses.

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Non-enzymatic recombination of RNA: Ligation in loops

Abstract: Our findings provide new data supporting the RNA World hypothesis and show the way of new RNA sequences emergence under prebiotic conditions.

Cited by 12 publications

References 78 publications

Random-sequence genetic oligomer pools display an innate potential for ligation and recombination

Random-sequence genetic oligomer pools display an innate potential for ligation and recombination

RNA knockdown by synthetic peptidyl-oligonucleotide ribonucleases: behavior of recognition and cleavage elements under physiological conditions

Recombination in Enteroviruses, a Multi-Step Modular Evolutionary Process

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