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ӳ����ý-MIT Seminars in Chemical Biology
February 24, 2025
ӳ����ý of MIT and Harvard

Speaker: Phil Holliger, MRC Laboratory of Molecular Biology
Talk title: Replicating RNA with RNA

Description:
A critical event in the origin of life is thought to have been the emergence of an RNA molecule capable of self-replication as well as mutation, and hence evolution towards ever more efficient replication. Although this ancestral replicase appears to have been lost, key aspects of RNA-catalyzed RNA replication can be studied “by proxy” with the use of modern RNA enzymes (ribozymes) generated by in vitro evolution.

Starting from the original RNA polymerase ribozyme (RPR) [1], we have evolved RPRs that are capable of the templated synthesis of another simple ribozyme [2] or long, unstructured RNA oligomers [3], and this activity is potentiated by simple Lys-rich peptides derived from the ribosomal cores [4]. However, none of these RPRs was capable of self-replication.

In this talk the speaker will describe the more recent engineering and de novo discovery of RPRs that utilize trinucleotide triphosphates as their main substrates. This unlocks the copying of even highly structured RNA templates and enables non-canonical reverse and primer-free replication modes [5] and - in the case of a recently discovered small RPR - the templated synthesis of its own (+) and (-) strands, an important step towards self-replication [6].

The speaker also discusses how structured media such as the eutectic phase of water ice [7] - as well as coupled pH / freeze-thaw cycles [8] – can aid RPR function and enable the replication of double-stranded RNAs over many cycles.