# Mechanisms of Mitotic Fidelity

> **NIH NIH R35** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $444,582

## Abstract

Project Summary
The major goal of mitosis is to distribute the genetic material accurately between two daughter cells. Defects
in meiosis or mitosis lead to aneuploidy, which is a significant cause of birth defects and is a hallmark of
tumorigenesis. Critical to this process is the mitotic spindle, which is a cellular macromolecular machine
tasked with both alignment and segregation of the genetic material. Even though the spindle structure and
molecular players are highly conserved across organisms, the detailed organization of the spindle and protein
function can vary even between cell types within an organism. This variation suggests that cells have evolved
multiple pathways to ensure the proper distribution of genetic material. My lab has a long-standing interest in
understanding how molecular motor proteins organize spindle structure, regulate microtubule dynamics in the
spindle, and contribute to accurate chromosome segregation during mitosis. These studies are important
because motor proteins not only play fundamental roles in spindle organization and function, but also because
they are often overexpressed in cancer cells and may be valuable targets for therapeutic development. In the
next five years, our studies will focus on three key questions. 1) How is molecular motor activity spatially and
temporally regulated? An important goal is to understand not only how molecular motors function individually,
but also how groups of motors cooperate with their binding partner to regulate spindle function. Our studies
will define critical networks between biochemical activities of motors and cellular readouts of that activity. 2)
How do regulated microtubule dynamics and centrosome clustering enhance mitotic fidelity? The current
model is that cancer cells generate low levels of aneuploidy to drive their survival while limiting severe
aneuploidy that would ensure cell death. We will uncover how key molecular motors impact mitotic fidelity by
dissecting their function in mitosis and DNA damage repair. In addition, we will examine how centrosome
clustering restricts severe aneuploidy in cells with amplified centrosomes. 3) How is accurate chromosome
segregation impacted by increased chromosome load in cells with altered ploidy? An important but
understudied problem is to elucidate how the normal complement of cellular proteins handles aneuploidy in
both normal and cancer cells and how changes in the relative expression levels of key players impact
accurate segregation of the genetic material. We will take advantage of our ability to generate cells with
different levels of ploidy to understand how changing expression of key molecular motors is impacted by
increased chromosome load and how that affects mitotic fidelity. Our proposed studies take advantage of our
toolbox of key molecules, rigorous biochemical assays, high quality imaging, and diverse model systems to
define the function of motors and regulatory networks that control mitotic fidelity. T...

## Key facts

- **NIH application ID:** 10405295
- **Project number:** 2R35GM122482-06
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Claire E Walczak
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $444,582
- **Award type:** 2
- **Project period:** 2017-06-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405295

## Citation

> US National Institutes of Health, RePORTER application 10405295, Mechanisms of Mitotic Fidelity (2R35GM122482-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10405295. Licensed CC0.

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