# Fundamental Biological Processes Under Torsion

> **NIH NIH R01** · CORNELL UNIVERSITY · 2021 · $299,763

## Abstract

Project Summary
 The helical nature of double stranded DNA (dsDNA) innately promotes the generation of
torsional stress during essential processes such as replication and transcription. In particular,
replication will inevitably generate DNA supercoiling which may braid or intertwine daughter
DNA strands, creating precatenanes. Such intertwining, if not properly resolved, results in DNA
damage, genome instability, and replication arrest. Though critical to cellular viability, these
problems are highly complex, posing significant barriers to experimentation. Thus our
mechanistic understanding has remained conspicuously limited. The work proposed here aims
to address the role that the torsional mechanical properties of chromatin play in determining the
formation and resolution of topological impasses, and in turn, the implications this has for
topoisomerase function. Aim 1 will establish methods to create, benchmark, and manipulate
both single and braided chromatin substrates. Since little is known about how topoisomerases
interact with chromatin substrates, Aim 2 will develop a novel assay to monitor topoisomerase
activity, in real time, and directly apply this approach to examine different topoisomerases to
determine their effectiveness in supercoiling removal and substrate preferences. This will also
allow investigation into how therapeutic agents impact topoisomerase activity. Finally, Aim 3 will
examine broadly replication generated torsion and topoisomerase binding sites genome wide.
To pursue these aims we will leverage state-of-the-art single molecule and genome wide
techniques – including established approaches and novel assays. The proposed research will
demonstrate the broad role of the intrinsic mechanical properties of chromatin in fundamental
biological processes and will have far-reaching impacts into the treatment of human disease
and the development of novel therapeutic agents.

## Key facts

- **NIH application ID:** 10226010
- **Project number:** 5R01GM136894-02
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** MICHELLE D. WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $299,763
- **Award type:** 5
- **Project period:** 2020-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226010

## Citation

> US National Institutes of Health, RePORTER application 10226010, Fundamental Biological Processes Under Torsion (5R01GM136894-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10226010. Licensed CC0.

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