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PhD Candidate, The University of Chicago


Investigations into enzymatic functions of RNA that were central to the origin of life

Chemistry of Life is written in the alphabet of genes, comprising letters of DNA, arranged in patterns to create biological messages. Sequences of DNA are transcribed into RNA which are used to make proteins. Proteins facilitate biochemical transformations required to sustain life, acting as enzymes or biocatalysts. However, it is generally accepted that RNA carried out the function of both proteins and DNA in their absence in primitive earth. This is the RNA World hypothesis, which proposes that building blocks of RNA, polymerized to form the first RNA molecules, billions of years ago. These molecules assumed different structures, dictated by the sequence of polymerization, and eventually new functions emerged as attributes of particular structures. Emergence of a particular enzymatic function, self-replication, triggered the conversion of non-living matter into life. I study the structure of RNAs that catalyze biochemical reactions, i.e. RNAs that function as enzymes (also Ribozymes). My work has unraveled mechanisms that ribozymes use to carry out their catalytic functions and have yielded useful models for studying the most primitive form of enzyme activity. While it is important to understand the strategies used by RNA enzymes in catalytic function, it is also essential to figure out how these functions emerged. With increasing diversity of RNA-based life, it was necessary for RNA molecules to acquire new functions, which likely occurred through mutations or random changes in its sequence. Novel functions emerged with new sequences adopting distinct structures. As a logical extension of my studies on ribozyme structure and function, the second part of my dissertation investigates the evolutionary mechanisms that could’ve led to the emergence of new enzyme functions in RNA. My research has unveiled evolutionary mechanisms that functional RNAs could’ve used to acquire new functions. Most random mutations create non-functional RNA sequences leading to evolutionary dead ends and therefore are not robust in introducing new functions on their own. I have discovered alternate mechanisms that could compliment mutational changes to explain the emergence of a wide range of enzymatic functions in RNA. My graduate research has uncovered fundamental structural principles guiding RNA enzyme function and delineated molecular mechanisms for the evolution of these functions that played essential roles in the origin of life and sustaining it right after its ‘birth’.