# Defining the physical and molecular basis of kinetochore structural maintenance under force

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $31,116

## Abstract

Project Summary/Abstract
 At cell division, the cell must accurately segregate its chromosomes to its two daughter cells. To
do so, the cell builds the spindle, with kinetochores connecting spindle microtubules to chromosomes.
The kinetochore is a macromolecular complex that performs both physical and biochemical roles: it
must resist and transmit force as microtubules pull on it to move chromosomes, and must also process
microtubule signals to control cell cycle progression. Errors in this process lead to aneuploidy, which
can then result in disease and birth defects.
 The kinetochore is assembled hierarchically: inner kinetochore proteins bind centromeric
histones, and outer kinetochore proteins assemble on this inner plate, eventually binding microtubules.
While much is known about the mammalian kinetochore’s architecture and composition, little is known
about its mechanics. Yet, its functions are mechanical – to segregate chromosomes. The kinetochore
is under varied forces, for example from different microtubule attachment states. How the kinetochore
structurally responds to different forces – and maintains its structure and function under force – is poorly
understood. In large part, this is because we cannot as yet purify the mammalian kinetochore in vitro,
where quantitative mechanical approaches exist. Recent progress in our lab to measure kinetochore
shape with high space and time resolution in vivo under natural forces brings this question within reach.
 Here, we propose to test physical and molecular models for how kinetochores maintain their
structure while under force. In Aim 1, we will test the hypothesis that kinetochore shape changes
originate in the inner kinetochore, and are due to high forces. We will do this by using live super
resolution imaging of inner and outer kinetochore proteins, and analyzing their shapes, movement, and
under how much force they are under (using centromere stretch as a proxy). In Aim 2, we will test
hypotheses on the molecular basis of kinetochore structural integrity under force: basal stability from
the centromere and lateral inner kinetochore reinforcement. To do so, we will use chemical and genetic
perturbations of candidate mechanisms, and use the same imaging approach as in Aim 1 to ask
whether these perturbations change the kinetochore’s shape under force.
 Overall, we aim to uncover the physical and molecular basis of the kinetochore’s ability to
maintain its structure and function under force. This will not only help us understand how the
kinetochore’s function emerges from its structure, but ultimately how its malfunctions can emerge from
structural failures in disease contexts. Key to this proposal, this work will provide training in biophysics,
quantitative microscopy, molecular approaches, mentorship, and science communication to graduate
student Vanna Tran towards her goals of becoming an independent group leader.

## Key facts

- **NIH application ID:** 10834397
- **Project number:** 3R35GM136420-04S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Sophie Dumont
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $31,116
- **Award type:** 3
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10834397

## Citation

> US National Institutes of Health, RePORTER application 10834397, Defining the physical and molecular basis of kinetochore structural maintenance under force (3R35GM136420-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10834397. Licensed CC0.

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