# Understanding and exploiting DNA topoisomerases in cancer biology

> **NIH NIH R35** · JOHNS HOPKINS UNIVERSITY · 2021 · $657,741

## 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 DNA 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 play a frontline role in cancer biology as factors that can
both maintain and disrupt genome integrity; they are also demonstrated drug targets for
treating cancer.
Our past research on eukaryotic topoisomerase II (topo II) has opened up new research
avenues for understanding cancer etiology and improving cancer treatment. The present
application will deliver groundbreaking solutions to key problems in the field, including how
certain classes of anti-topo II drugs act on the enzyme, how topo II is localized to key sites
of action where it resolves potentially deleterious chromosomal topologies, and how
aberrant topo II activity can promote DNA damage and genetic instability. We will also
investigate innovative concepts and highly significant lines of inquiry raised by our new
findings, such as how metabolites produced by the TCA cycle control topo II function.
Our approach is distinguished by a comprehensive blend of biochemical, structural,
computational, cell-based, and chemical biology methodologies. High-impact outcomes
will include defining how topo II appropriately localizes with chromatin and partner proteins
to mitigate its natural DNA-damaging potential, establishing how the specificity of anti-topo
II agents can be improved to enhance their utility in cancer treatment, and revealing the
potential for natural amino-acid sequence variation in type II topoisomerases to destabilize
human chromosomes and act as cancer drivers. Past progress and unpublished findings
establish the feasibility of our planned goals.

## Key facts

- **NIH application ID:** 10296437
- **Project number:** 1R35CA263778-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** James M. Berger
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $657,741
- **Award type:** 1
- **Project period:** 2021-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296437

## Citation

> US National Institutes of Health, RePORTER application 10296437, Understanding and exploiting DNA topoisomerases in cancer biology (1R35CA263778-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10296437. Licensed CC0.

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