# Molecular Analysis of Chromosome Segregation

> **NIH NIH R35** · UNIVERSITY OF WASHINGTON · 2020 · $730,827

## Abstract

Project Summary
Life depends on the accurate transmission of genetic material at each cell division. Errors in this process
lead to aneuploidy, which is implicated in oncogenesis, birth defects and cell death. Duplicated
chromosomes are captured and segregated by a microtubule-based molecular machine, the mitotic
spindle. The spindle is bipolar and each spindle pole carries an exact complement of chromosomes to
each daughter cell. During mitosis, microtubules nucleate from the poles and capture and organize the
chromosomes. Kinetochores, large multiprotein organelles located at the centromeric DNA, bind the
microtubules and anchor the chromosomes to the poles. Our work focuses on each end of the
microtubule, the spindle poles and the kinetochores.
Spindle morphogenesis requires spatially controlled microtubule nucleation. Using a combination of
reconstitution and in vivo analysis, we will test hypotheses that address how microtubule nucleation is
activated and spatially regulated.
Kinetochores attach chromosomes to microtubules with a striking combination of strength and plasticity.
The attachments are mobile and robust under tension, but can also rapidly destabilize in response to
regulatory signals. As such, the kinetochore is at the center of an error correction mechanism that repairs
incorrect attachments sensed by a lack of ‘proper’ tension. The identification of the proteins that are
under tension, the measurement of the strength of the linkages and the requirements for the full strength
of attachments are together the second focus of this project.
We have found that individually no kinetochore protein binds the microtubule with strength or longevity.
To reconstitute the full strength of microtubule attachment exhibited by native kinetochores requires
synergy between proteins in contact with the microtubule with proteins within the interior of the
kinetochore. We will use a reconstitution-based approach and in vivo analysis to test the contribution of
affinity, avidity and geometry to this synergy. In this way we will understand how the whole achieves
greater properties than the sum of the parts. In addition, by exploiting our reconstituted kinetochore, we
will test hypotheses for how the tension signal that triggers error correction is transmitted from the
kinetochore and received by the repair mechanisms.

## Key facts

- **NIH application ID:** 9880435
- **Project number:** 5R35GM130293-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Trisha Davis Muller
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $730,827
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880435

## Citation

> US National Institutes of Health, RePORTER application 9880435, Molecular Analysis of Chromosome Segregation (5R35GM130293-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9880435. Licensed CC0.

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