# Chromosome dynamics and organizations necessary for faithful chromosome segregation

> **NIH NIH R35** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $94,093

## Abstract

PROJECT SUMMARY
Cell division is a conserved process by which replicated chromosomes are equally partitioned into two daughter
cells. Errors in this process often result in gains or losses of chromosomes, known as aneuploidy, which can
cause and promote tumors and developmental diseases. During mitotic progression, chromosomes dynamically
change their positions in a force-dependent manner via forces generated at kinetochores, macro-molecular
protein structures built on centromeric chromatin that serves as platforms for microtubule assembly. While
chromosome territories, regions preferentially occupied by specific chromosomes in interphase nuclei, have
been established and are known to be involved in gene regulation and genomic protection, the presence and
function of chromosome organization in mitosis have not been adequately explored. Our long-term goals are to
characterize “mitotic chromosome territories” in mammalian cells and to uncover the function behind
spatiotemporal regulation of both chromosome organization and kinetochore dynamics in ensuring faithful
chromosome segregation. In this proposal, we will test the hypothesis that there exist chromosome organizations
in mitosis as in interphase nuclei using a super-resolution microscopy method we recently developed, which will
allow us to identify full sets of individual chromosomes and determine their spatial organization in mammalian
cells. If there exist mitotic chromosome territories, we will explore how and when they are established and their
evolution throughout mitosis. We also hypothesize that major mitotic defects (unaligned chromosomes, lagging
chromosomes, and chromosome bridges) are associated with improper chromosome organization. We will
examine this hypothesis by identifying which chromosomes are involved in each defect with increased frequency
and determine their positionings. Mitotic cells have two major pathways for correcting mitotic errors, mediated
by Aurora A or Aurora B kinases. Both kinases are spatially regulated and phosphorylate a highly conserved
microtubule-binding kinetochore protein, Ndc80/Hec1, to destabilize improper microtubule bindings for
promotion of error correction and regulation of SAC (spindle assembly checkpoint) activity. Aurora A-mediated
error corrections require proximity of erroneous chromosomes to the spindle poles, where Aurora A is
concentrated. On the other hand, Aurora B-mediated error corrections depend on dynamic deformations of
kinetochores. These suggest that mitotic chromosome positioning, coupled with kinetochore dynamics,
orchestrate the cooperation between Aurora A and Aurora B-mediated error correction machineries. We will
dissect the contributions of chromosome positioning and kinetochore dynamics towards Aurora A and Aurora B
error corrections using force-calibrated microneedles and a semi-automated, quantitative microscopy analysis
software that we recently developed called the 3D speckle analyzer (3D-Speckler). Our proposed wor...

## Key facts

- **NIH application ID:** 11035830
- **Project number:** 3R35GM147525-02S2
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Aussie Suzuki
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $94,093
- **Award type:** 3
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11035830

## Citation

> US National Institutes of Health, RePORTER application 11035830, Chromosome dynamics and organizations necessary for faithful chromosome segregation (3R35GM147525-02S2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11035830. Licensed CC0.

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