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Repeating cycles of chemically-driven RNA replication within model protocells

Project description

Insight into chemically driven nucleic acid replication

DNA replication represents a major evolutionary event as it allows organisms to pass genetic information to their offspring. However, our understanding of how nucleic acid replication occurred without genetically encoded enzymes is poor. The EU-funded RNA-Rep project is testing the hypothesis that non-enzymatic RNA replication can be accommodated by chemicals and that the resultant double-stranded molecule is separated by heating. Given that high temperatures induce membrane damage and leakage, researchers are investigating the scenario that single RNA strands are encompassed in protocellular compartments. The project will provide unprecedented knowledge on the mechanism of nucleic replication before the onset of Darwinian evolution.

Objective

Deciphering how nucleic acids replicated in the absence of genetically encoded enzymes is of critical importance to understanding the onset of Darwinian evolution. While much effort has been put into developing chemically-driven copying of RNA exploiting activated monomers, many unsolved issues stand in the way of achieving repeated cycles of non-enzymatic RNA replication. Non-enzymatic copying of a template strand results in the formation of an RNA duplex, which must then be denatured in order for subsequent rounds of replication to take place. Although RNA strands can be separated by heating, re-annealing kinetically outcompetes slow non-enzymatic copying, thus inhibiting RNA amplification. One unexplored solution to this problem is to physically separate melted strands of RNA so that re-annealing is not possible. Since all known living systems exploit lipid membranes, we propose to investigate whether protocellular compartments can facilitate the emergence of simplistic chemical systems that amplify RNA. Specifically, high temperatures are known to induce both RNA strand separation and bilayer defects, ultimately allowing for the partial leakage of RNA. If the transition temperature of the lipid membrane is higher than the melting temperature of the RNA, then subsequent slow cooling would recover the original impermeability of the membrane and give rise to a fraction of protocellular structures containing stochastic numbers of single RNA strands. At this stage, feeding with permeable activated short (oligo)nucleotides would lead to renewed copying of RNA. This highly original and multidisciplinary project combines the strength of organic and supramolecular chemistry to optimise prebiotic compartments with the power of in situ non-enzymatic RNA biochemistry to yield a project of excellent, innovative science that will exploit my expertise in protocellular systems while providing me extensive training in organic synthesis, chemical biology and biophysics.

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Coordinator

UNITED KINGDOM RESEARCH AND INNOVATION
Net EU contribution
€ 224 933,76
Address
Polaris house north star avenue
SN2 1FL Swindon
United Kingdom

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Region
South West (England) Gloucestershire, Wiltshire and Bristol/Bath area Swindon
Activity type
Research Organisations
Links
Other funding
€ 0,00