Krastan Blagoev
$549,701
Harvard University
Massachusetts
Mathematical and Physical Sciences (MPS)
The integrity of the genetic information, carried by large chain molecules called nucleic acids (DNA and RNA), is vital for all organisms on Earth. When exposed to ultraviolet (UV) sunlight, DNA and RNA can form structural defects, which damage their function, cause mutations, or in severe cases - lead to cell death. But sunlight can be also a healer. The PI’s lab recently discovered that some short RNA strands can self-repair in a manner very similar to DNA. The PI observed that short RNA strands do so by developing states under UV-sunlight, which last long enough to transfer an electron to the damaged site and heal it. This discovery of RNA self-repair opens the door for a number of experimental projects on RNA’s origins and non-enzymatic replication, on RNA sequence selectivity, on tRNA function, etc. From a practical perspective, these results also have implications for how cells handle RNA damage in modern organisms, so the PI pay close attention to potential biomedical applications. Therefore, this award promotes progress in fundamental science, as well as advances in national health issues, as the handling of RNA damage by cells and viruses has become a newly active area since the pandemic. While advancing discovery, this award will also contribute to the education and training of future scientists and engineers as well. The research-based education of undergraduate and graduate students in our lab, and the high representation of women in the PIs lab will broaden participation in achieving these goals. <br/><br/>This award project plans to elucidate the mechanism of the self-repair process in RNA and to extend its generality by experimenting with an array of RNA sequences, as well as with non-canonical nucleotides like Inosine. Working with short two- and four-base sequences is just the necessary first step. In addition to longer length, the investigators will explore both the base selection and the sequence directionality. The latter turns out to make a difference, as the investigators recently showed with DNA sequences of GAT=T versus T=TAG, assigning this disparity to the importance of different stacking overlap between the G and A bases. This award is exciting and important because no existing RNA photolyase enzymes are known, and the results from this award may shed light on how cells handle damaged RNA with mechanisms that are very different from DNA repair activity as known to-date. Therefore, some results from this award may have implications to physiology and medicine. On the other hand, as there were no enzymes during the emergence of life, this award will contribute to understanding the prebiotic sequence selectivity in RNA’s early functions in prebiotic chemistry and/or as information carrier in translation or replication. The investigators will explore the long-lived charge-transfer states in tRNA-analogs and similar RNA oligos as potential functional switches in the early evolution of translation. The ability of RNA and cofactors, like NADH, to form UV-induced charge-separated states and to transfer charge in a selective manner is not only intriguing but could be of paramount importance to the emergence of primitive cell functions during the origins and early evolution of life. What is often viewed simply as damage (or lesion), could well be a life-saving functionality for a primitive cell surviving on low-fidelity non-enzymatic RNA replication. With this new approach to nucleic acid UV-induced damage, the investigators will pursue a number of experiments into the emergence of functionality at the origins of translation (e.g., aminoacylation of RNA) and non-enzymatic RNA replication.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.