Towards Self-Replicating Informational Polymers

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Towards Self-Replicating Informational Polymers

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Title: Towards Self-Replicating Informational Polymers
Author: Prywes, Noam ORCID  0000-0003-2526-2392
Citation: Prywes, Noam. 2016. Towards Self-Replicating Informational Polymers. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
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Abstract: The capability to transmit information from generation to generation is an essential feature of life. In all terrestrial life, DNA and RNA contain information in the form of a sequence of monomers and are copied in every generation. The RNA world hypothesis posits that there was a time in the history of life when all cellular functions were accomplished by RNA catalysts. However, the initial emergence of those RNA catalysts is not yet fully understood.

Nonenzymatic RNA polymerization has been proposed as a potential stepping- stone from prebiotic chemistry to the RNA world. In searching for alternatives to the chemically trapped triphosphate nucleotides found in modern biology, chemical modifications of RNA have been discovered that allow for the copying of RNA. However, the copying of sequences rich in adenine and uracil residues remains a significant challenge. In chapter 2 we use chemically activated oligonucleotides as catalysts to copy all four monomers sequentially, potentially creating a route for the copying of any sequence without a polymerase and contributing to a model for the emergence of evolution.

Replacing uracil with 2-thiouracil and 2-thiothymine, modified forms of uracil found in modern life, has proven to improve the reactivity and fidelity of nonenzymatic RNA polymerization. In chapter 3, we tested these alternatives to uracil as substrates and components of an RNA polymerase ribozyme. We discovered that they were superior in the context of ribozyme mediated RNA polymerization both in terms of faster rate and higher fidelity. We then synthesized ribozymes in which every instance of uracil was replaced by either 2-thiouracil or 2-thiothymine and found them to retain some activity. We hypothesize that these alternative nucleobases could have conferred significant benefits to early life forms.

To explore alternative genetic systems to DNA and RNA, in chapter 4 of this thesis we synthesized an organic-soluble copolymer with two different monomers capable of reversible covalent bond formation with one another. We show that information copying is possible with this polymer by synthesizing a polymer with a sequence complementary to a template while it is still covalently bound to that template, demonstrating that nucleic acids are not the only molecules capable of information storage and replication.

Together, these results assist in the construction of artificial life and expand the possibilities for the emergence of life.
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