# Error Correction in Mammalian Mitosis: Defining Physical Cues and Integration Mechanisms

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $42,137

## Abstract

Project Summary/Abstract
Errors in chromosome segregation give rise to aneuploidy, a hallmark of cancer. Breakdown of mitotic fidelity
correlates with both tumor stage and patient drug resistance. Identifying mechanisms that prevent errors in
chromosome segregation, and determining how they go wrong in cancer, are essential to developing therapies
to either decrease or increase segregation error rates in cancer.
 The kinetochore attaches chromosomes to spindle microtubules. It segregates chromosomes and
monitors their microtubule attachments, stabilizing correct attachments and destabilizing incorrect ones. We
now know nearly all mammalian kinetochore proteins, and many have dysregulated expression in cancer. How
does the kinetochore detect and correct attachment errors, and fail to do so in cancer? The idea that tension
from bi-orientation signals correct attachments is decades-old, originating in Nicklas' pioneering experiments in
grasshopper spermatocytes. Yet, how the kinetochore monitors tension and robustly integrates information
across its many bound microtubules to regulate attachment stability is not known. In large part, this is due to
challenges in applying tension on kinetochores inside cells, in quantitatively tuning kinetochore composition,
and in imaging short-lived error correction events in real-time. Our laboratory has recently overcome these
challenges, uniquely positioning us to answer these questions. Notably, two candidate kinetochore proteins
have been proposed for sensing tension, the kinase AurKB and microtubule polymerase chTOG, and the
expression of both is dysregulated in cancer, as is that of the main microtubule binder Hec1.
 Here, we test defining hypotheses on how normal and cancer cells detect and correct mitotic errors,
combining high resolution 3D live-cell imaging, state-of-the-art physical perturbations, and molecular tools in
normal and breast cancer cells. In Aim 1, we test the hypothesis that AurKB and chTOG sense tension. We
use microneedles to directly apply force to kinetochore-microtubules, measure how attachment stability
responds, and assess how these proteins' dysregulated expression alters this response in cancer. In Aim 2, we
test models for whether microtubules respond independently or cooperatively to attachment cues such as
tension, and test the hypothesis that Hec1 overexpression in cancer cells leads to hyper-stable attachments
that may be more challenging to properly correct. We do so by quantitatively tuning kinetochore microtubule
binding capacity using mixed Hec1 mutants, and measuring microtubule attachment lifetime using photomarks.
 In defining critical mechanisms for correcting mitotic errors, and how they are modified in cancer, we
expect to identify adapted mechanisms of error correction in cancer cells. For example, some cancer cells may
be deficient in error correction, leading to aneuploidy, or have improved error correction to compensate for
extra chromosomes. Mechanisms uniquely...

## Key facts

- **NIH application ID:** 10447001
- **Project number:** 5F31CA265136-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Megan Kaiulani Chong
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $42,137
- **Award type:** 5
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447001

## Citation

> US National Institutes of Health, RePORTER application 10447001, Error Correction in Mammalian Mitosis: Defining Physical Cues and Integration Mechanisms (5F31CA265136-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10447001. Licensed CC0.

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