# Control of Chromosome Segregation by DNA Topoisomerase II

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $292,871

## Abstract

Abstract
Chromosome segregation errors result in aneuploidy which causes birth defects and cancer. We have
defined a new mitotic Topo II-responsive control (TRC) in yeast that delays the cell cycle when Topo II
activity is insufficient for accurate chromosome segregation. This TRC mechanism is conserved in human
cells, but has not been extensively studied. Activation of the TRC is triggered by defects in the strand
passage reaction of Topo II, when the enzyme transits too slowly through its structural conformations. TRC
activation also requires the catalytically inert C-terminal domain of Topo II, which contains novel protein-
protein interaction motifs that bind to TRC signaling proteins. The central model is that aberrant strand
passage may structurally transfer from the catalytic core of Topo II to the C-terminal domain which functions
as a signal-generating scaffold to halt the cell cycle. The conservation between the human and yeast TRC
responses provides unique opportunities to identify the TRC components and to reveal the mechanism of
TRC activation. We aim to determine the cellular/genomic sites of TRC activation, the signaling molecules
involved and the mechanism of TRC activation by the C-terminal domain of Topo II. The results of these
studies will impact opportunities for translational research because we will identify new potential therapeutic
targets. Our findings will also impact the use of widely prescribed therapeutic drugs that target Topo II
because we will gain mechanistic insight into cellular responses to Topo II inhibition. The preliminary data
and newly developed experimental tools place us in a unique position to determine the conserved
mechanism of this scarcely studied mitotic control.

## Key facts

- **NIH application ID:** 10085253
- **Project number:** 5R01GM130858-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** DUNCAN J. CLARKE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $292,871
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085253

## Citation

> US National Institutes of Health, RePORTER application 10085253, Control of Chromosome Segregation by DNA Topoisomerase II (5R01GM130858-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10085253. Licensed CC0.

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