# Mechanisms of Kinetochore-Microtubule Attachment and Regulation

> **NIH NIH R35** · COLORADO STATE UNIVERSITY · 2024 · $453,118

## Abstract

Project Summary
The goal of mitotic cell division is to produce two cells from one and to ensure that each daughter cell inherits
an exact copy of the original genetic material. When mitosis malfunctions, a common result is aneuploidy, in
which cells contain the incorrect number of chromosomes. This impacts human health, since aneuploidy is a
leading cause of birth defects and is implicated in cancer initiation and progression. The fidelity of mitosis
depends on kinetochores, which are structures built at defined regions of chromosomes called centromeres.
Kinetochores have several essential functions, including the following: (1) they connect chromosomes to spindle
microtubules, (2) they regulate the strength of these connections, and (3) they ensure that cells do not exit mitosis
if chromosomes are incorrectly attached to microtubules (via the spindle assembly checkpoint). Our lab focuses
on understanding kinetochores, and specifically how they establish and regulate attachments to microtubules.
Our lab also investigates how tumorigenesis results in kinetochore defects, and how these defects lead to cancer
cell-specific vulnerabilities that can be exploited for cancer therapies. The first two projects in the proposal aim
to uncover the mechanisms cells use to establish and regulate kinetochore-microtubule attachments in human
cells. Based on our recent findings, we have generated new hypotheses for how the Aurora family of kinases
(i.e., Aurora A, and Aurora B) impact kinetochore-microtubule attachment stability. A significant obstacle that has
hindered progress in understanding how kinetochore kinases precisely regulate kinetochore-microtubule
attachments is the lack of tools that permit unobtrusive tracking of the dynamics of these kinases and their
activities at kinetochores with high spatial and temporal resolution. We have overcome this by developing
methods to generate genetically-encoded, fluorescently-tagged, antibody-based probes that can be used to track
these phenomena in living cells. We will use this approach to generate phosphorylation “sensors” that recognize
active, phosphorylated forms of Aurora A and Aurora B kinases, as well probes directed to their target substate
sites at kinetochores. We will use these tools – and generate new ones – to discover how kinetochore kinases
regulate kinetochore-microtubule attachment stability throughout mitosis to ensure successful chromosome
segregation. A related project will address how kinetochore-microtubule attachment status is communicated to
the checkpoint. For this, we will employ our phospho-sensors, super-resolution imaging, and a newly-developed
in vitro chromosome capture assay. Finally, we made the recent discovery that hyperactive signaling by the RAS
and MAPK pathways over-stimulates kinetochore kinases to induce kinetochore defects and cancer cell-specific
vulnerabilities in laboratory-transformed cells and glioblastoma tumor isolates. We aim to identify the targets of
MAPK in ...

## Key facts

- **NIH application ID:** 10765249
- **Project number:** 2R35GM130365-06
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Jennifer G DeLuca
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $453,118
- **Award type:** 2
- **Project period:** 2019-03-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765249

## Citation

> US National Institutes of Health, RePORTER application 10765249, Mechanisms of Kinetochore-Microtubule Attachment and Regulation (2R35GM130365-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10765249. Licensed CC0.

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