# Kinetochore Specification and Function

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $116,074

## Abstract

PROJECT SUMMARY
For the development of an organism from a single cell, the genome must be duplicated and precisely distributed
during every cell division. Given the astronomical number of cell division events involved in building and
maintaining organisms (by one estimate, the adult human body is made up of 40 trillion cells, with at least a
couple of trillion dividing every day), it becomes critical that the distribution of the replicated genome to daughter
cells, a process known as chromosome segregation, occurs with extremely high accuracy. Errors in chromosome
segregation underlie birth defects/infertility and are sufficient to trigger the genomic havoc that is a hallmark of
cancer. Thus, understanding the mechanisms by which cells ensure accurate chromosome segregation during
cell division has both fundamental and therapeutic significance. Our work is focused on kinetochores, protein
machines that assemble on mitotic chromosomes to orchestrate their segregation. Kinetochores coordinate
multiple microtubule-interfacing activities that collectively orient and segregate chromosomes, while also
integrating mechanical events with signaling mechanisms that control the decision to either remain in or exit from
mitosis. Our early work identified a conserved set of proteins, referred to as the KMN network (for Knl1 complex,
Mis12 complex, Ndc80 complex) that lies at the heart of these coordinated kinetochore functions. In Aim 1, we
focus on the ability of kinetochores to both accelerate and delay exit from mitosis, which we propose optimizes
mitotic duration to allow sufficient time for all chromosomes to connect to the spindle, while also minimizing time
spent in a vulnerable phase when major cellular functions such as transcription, translation and secretion are
downregulated. The work we propose tackles major open questions related to this duality of mitotic timing control
by kinetochores. The primary mechanical activity of the kinetochore is to couple to dynamic spindle microtubules.
Several distinct microtubule-interfacing activities concentrate at kinetochores as well as on mitotic chromatin,
which makes analysis of chromosome-microtubule interactions challenging in a cellular context. In Aim 2, we
describe a "blank slate–add back" approach, in which we eliminate all microtubule-interfacing activities on mitotic
chromosomes and then add them back in isolation. This approach complements traditional loss-of-function
analysis and will be used to study the microtubule-interfacing activities at kinetochores that orient and center
chromosomes on the spindle and that shut of the signal that prevents mitotic exit until microtubule attachments
are made. Finally, to achieve accurate segregation, kinetochore-microtubule interactions must be tightly
regulated. In Aim 3, we focus on the poorly understood regulatory mechanism by which a spindle pole-generated
gradient of the mitotic kinase Aurora A controls kinetochore-microtubule attachments. As Aurora A is...

## Key facts

- **NIH application ID:** 10797364
- **Project number:** 3R01GM074215-19S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Arshad Desai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $116,074
- **Award type:** 3
- **Project period:** 2005-05-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10797364

## Citation

> US National Institutes of Health, RePORTER application 10797364, Kinetochore Specification and Function (3R01GM074215-19S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10797364. Licensed CC0.

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