# Regulation of Chromosome Segregation in Human Cells

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $489,753

## Abstract

PROJECT SUMMARY/ABSTRACT
To ensure genome stability, the spindle assembly checkpoint (SAC) delays anaphase
until all pairs of kinetochores are attached to the ends of microtubule fibers from opposite
spindle poles. In addition, improper chromosome-spindle linkages are selectively
destroyed before anaphase. Through genome editing and chemical genetics, we found
that the SAC kinase Mps1 controls both responses. Through large-scale
phosphoproteomics, we discovered novel Mps1-regulated substrates at the kinetochore,
including the Ska complex (which helps the Ndc80 complex grip onto dynamic
microtubule ends) and the coatomer-related RZZ complex (which integrates Mad1-Mad2
dependent SAC signaling and dynein-dependent transport). In Aim 1, we investigate how
Mps1 affects the synergistic interactions of the Ska and Ndc80 complexes on dynamic
microtubules, both in cells and in reconstituted in vitro systems. In Aim 2, we dissect how
Mps1 activates the RZZ complex for Mad1-Mad2 recruitment, long-term SAC arrest, and
structural expansion of unattached kinetochores. In Aim 3, we develop a new chemical-
genetic system for Aurora A, a mitotic kinase that remains difficult to study because
current inhibitors with Aurora A selectivity in vitro nonetheless cross-inhibit Aurora B at
bioactive concentrations in vivo. Together these studies will reveal how kinetochore
structure, microtubule attachment, and SAC signaling evolve during mitosis, in order to
maximize the probability of error-free chromosome segregation. Ultimately this
information will empower development of therapeutic agents that target aneuploidy-
associated diseases such as cancer.

## Key facts

- **NIH application ID:** 10180979
- **Project number:** 5R01GM094972-17
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Prasad V Jallepalli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $489,753
- **Award type:** 5
- **Project period:** 2005-07-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180979

## Citation

> US National Institutes of Health, RePORTER application 10180979, Regulation of Chromosome Segregation in Human Cells (5R01GM094972-17). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10180979. Licensed CC0.

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