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Understanding Substrate Selection and Functional Output of Bacterial Type IIA Topoisomerase Orthologs and Paralogs
- Tretter, Elsa
- Advisor(s): Berger, James M
Abstract
Key processes in the cell, such as replication, transcription and repair, result in the
supercoiling of genomic DNA, which is resolved by molecular machines known as
topoisomerases. Type II DNA topoisomerases remodel DNA by passing one duplex DNA
strand through a transient break in a second duplex DNA strand. Type II topoisomerases
achieve DNA cleavage and religation with high fidelity by the coordination of multiple
domains. Achilles heel-like enzymes, which are indispensible to cells, topoisomerases are
targeted by numerous antibiotics and cancer therapeutics, necessitating a thorough
understanding of their structure and function.
Previously thought to be a uniform group of enzymes, a number of bacterial type
IIA topoisomerase paralogs have been identified with highly specialized functions but it
is not understood how each paralog recognizes and acts on unique DNA topologies. The
central hypothesis of this project is that the bacterial type IIA DNA binding domain,
termed the C-terminal domain (CTD), is principally responsible for substrate
identification and functional output of type IIA topoisomerases. I performed an array of
structural and biochemical studies on three unique bacterial type IIA topoisomerases to
understand how the CTD controls type IIA topoisomerase activity. The work presented in
this dissertation identifies novel type IIA topoisomerase evolutionary paths, characterizes
novel regulatory mechanisms, and introduces evidence that many characteristics refine
enzyme activity.
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