UC Berkeley

Abstract

Regulation of Bacterial Type IIA Topoisomerases

by

Seychelle Monique Vos

Doctor of Philosophy in Molecular and Cell Biology

University of California, Berkeley

Professor James M. Berger, Chair

DNA topoisomerases are ubiquitous and essential enzymes that maintain the supercoiling homeostasis of chromosomes. Decades of research have elucidated how topoisomerases manipulate DNA to introduce or remove supercoils. Recently it has become apparent that these enzymes are highly regulated by cells, often through direct physical interactions with other proteins involved in diverse cellular processes such as replication, chromosome condensation, transcription, and repair. It is largely unknown how these interactions affect enzyme function and localization in cells.

To gain a better understanding of topoisomerase regulation, I have explored some of the intrinsic and extrinsic mechanisms bacteria use to control their type IIA topoisomerases, topoisomerase (topo) IV and gyrase. This work has revealed intrinsic features that contribute to substrate discrimination by topo IV, determined how a condensin homolog binds and activates topo IV, and uncovered a novel proteinaceous mechanism to inhibit gyrase function. These initial studies provide a framework for understanding how gyrase and topo IV function are integrated into the broader context of the cell through enzyme specific modifications and associations and may provide novel targets for small molecule inhibitors.