# Structural and Biochemical Analyses of Type II DNA Topoisomerases

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $454,709

## Abstract

ABSTRACT
The appropriate control of DNA topology has a major impact on the stability and flow of
genetic information. The present application focuses on type II topoisomerases,
molecular machines that modulate DNA supercoiling and remove chromosome
entanglements by catalyzing the ATP-dependent transport of one DNA duplex through
another. Type II topoisomerases are critical for maintaining gene expression,
chromosome superstructure, and genome integrity; they also serve as frontline drug
targets for treating infectious disease and cancer.
During the prior project period, we gained several new insights into the mechanism,
regulation, and DNA damage propensity of type II topoisomerases. These efforts open
up three new research opportunities centered on complementary but non-interdependent
aspects of type II topoisomerase action that will advance both fundamental biological
knowledge and therapeutic intervention. Aim 1 seeks to explain the long-unresolved
question of how type II topoisomerases link ATP-dependent allosteric responses to the
selective engagement and release of multiple DNA segments, and to illuminate how a
system responsible for initiating meiotic recombination co-opted and modified a
topoisomerase scaffold to generate DNA breaks for promoting chromosome exchange.
Aim 2 will break new ground in understanding the regulation of eukaryotic topo II,
uncovering natural metabolites that control enzyme activity as means to modulate
replication, transcription, and chromosome organization processes that are sensitive to
DNA topology. Aim 3 will determine how the action of human topo IIβ drives aberrant
DNA damaging events and how naturally-occurring mutations may further potentiate this
detrimental activity.
Our approach is distinguished by a comprehensive blend of biochemical, structural,
computational, cell-based, and chemical biology methodologies. Past progress and
unpublished findings provide data to establish feasibility for the proposed effort. Our
studies will impact multiple fields, from the study of molecular machines and the control
of DNA dynamics, to understanding how topoisomerase activity and its regulation
support specific physiological needs and promote human reproduction and health.

## Key facts

- **NIH application ID:** 9850936
- **Project number:** 5R01CA077373-23
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** James M. Berger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $454,709
- **Award type:** 5
- **Project period:** 1999-05-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850936

## Citation

> US National Institutes of Health, RePORTER application 9850936, Structural and Biochemical Analyses of Type II DNA Topoisomerases (5R01CA077373-23). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9850936. Licensed CC0.

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