# Mechanisms of kinetochore-microtubule attachment and regulation

> **NIH NIH R35** · COLORADO STATE UNIVERSITY · 2023 · $105,147

## Abstract

Project Summary
The goal of cell division is to reliably produce two identical daughter cells, each with an exact copy of the
original genetic material. When this process goes awry, a common result is aneuploidy, which is a leading
cause of birth defects and a key characteristic of cancer. Mitotic cell division critically depends on kinetochores,
structures that orchestrate chromosome segregation and integrate all aspects of the mitotic machinery to
ensure mitosis is executed with high fidelity. Kinetochores physically connect chromosomes to spindle
microtubules (MTs), and they regulate the strength of these connections so that erroneously-attached MTs are
released, and correctly-attached MTs are stabilized. Importantly, kinetochores ensure that cells do not exit
mitosis if chromosomes fail to attach, or are incorrectly attached, to MTs. Much progress has been made in
identifying the kinetochore proteins that participate in these processes; however, how these molecules function
in concert to ensure the accuracy of chromosome attachment and segregation, and to ensure timely mitotic
progression remains poorly understood. Our lab has been instrumental in defining how kinetochores regulate
MT attachment, and how this fundamental aspect of mitosis is integrated into controlling cell cycle progression.
Additionally, our lab has begun to make significant inroads to understanding how oncogenic transformation
leads to deregulated kinetochore function, and how these defects lead to cancer cell-specific vulnerabilities
that can potentially be exploited for cancer therapies. Our expertise in studying kinetochore function in
combination with our newly developed experimental approaches – especially those that provide increased
spatial and temporal resolution of kinetochore proteins – puts us in a strategic position to resolve how
kinetochores ensure accurate chromosome segregation and drive mitotic progression. In the next five years,
our research will focus on four areas. We will: (1) Examine the mechanisms of kinetochore-MT attachment
regulation using biochemical and cell biological tools, as well as new assays to track the dynamics of specific
phosphorylation events in cells with high temporal resolution; (2) Investigate how Aurora B kinase, the “master”
regulator of attachment, is recruited to discrete centromere and kinetochore regions with precise temporal
control using in-cell mutagenesis approaches, proximity-dependent interaction/mass spectrometry analysis,
and phospho-modification tracking techniques; (3) Probe how kinetochore-MT attachment status is
communicated to the spindle assembly checkpoint, in part by using super-resolution imaging to map the
changes in kinetochore architecture that occur upon stable MT attachment; (4) Determine how oncogenic
signaling leads to kinetochore-MT attachment deregulation using a tumor progression model system built from
primary cells. In sum, our studies will provide critical insight into the fundamental mechanism...

## Key facts

- **NIH application ID:** 10795240
- **Project number:** 3R35GM130365-05S1
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Jennifer G DeLuca
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $105,147
- **Award type:** 3
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10795240

## Citation

> US National Institutes of Health, RePORTER application 10795240, Mechanisms of kinetochore-microtubule attachment and regulation (3R35GM130365-05S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10795240. Licensed CC0.

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