# Mechanisms of Kinetochore Assembly

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $331,390

## Abstract

Project Summary
Cells must accurately segregate their chromosomes into daughter cells at each division in order
for cells to reproduce and proliferate. Mistakes in chromosome segregation lead to imbalances
in chromosome copy number termed aneuploidies that are hallmarks of cancer, that cause
developmental diseases such as Down syndrome and that are a primary cause of miscarriage.
This work is focused on understanding how cells maintain a normal chromosome copy number
during the process of chromosome segregation. The key regulator of chromosome segregation
is the chromosomal kinetochore. The kinetochore is the site on each chromosome that attaches
to the microtubules of the mitotic spindle so that chromosome can move to daughter cells during
cell division. Kinetochores also monitor proper chromosome alignment through the mitotic
checkpoint to ensure that each daughter cell gets one copy of each chromosome. The
foundation for kinetochore formation is a region of the chromosome termed the centromere.
Centromeres are a chromatin domain that is uniquely determined by the presence of a variant
histone termed centromere protein A (CENP-A). The formation of centromeres is epigenetically
determined by the presence of CENP-A in chromatin and once a centromere is formed it can be
stably maintained regardless of the DNA sequence on which it is built. CENP-A chromatin is
essential for centromere and kinetochore formation and mutation or loss of CENP-A results in
centromere loss and chromosome missegregation. We are studying the mechanisms that
assemble and maintain CENP-A chromatin and how CENP-A chromatin is recognized to build
the centromere and kinetochore. In our first specific Aim we dissect the biochemical
mechanisms that build CENP-A nucleosomes at the right time and place in the chromosome. In
particular, we focus on understanding how a key regulator of new CENP-A nucleosome
formation, the Mis18 complex, is properly targeted to centromeres and how it functions in
CENP-A assembly. In our second Aim we explore the function of DNA sequences in centromere
formation. Although CENP-A is the primary epigenetic determinant of centromere function the
sequence of the DNA at centromeres promotes efficient centromere formation and
maintenance. We test whether specific DNA sequences stimulate CENP-A assembly and
whether DNA or RNA molecules actively regulate new CENP-A nucleosome formation.
Together our approach defines the basis for centromere formation and how the proteins of the
centromere give rise to the properties required for chromosome segregation in mitosis.

## Key facts

- **NIH application ID:** 10111522
- **Project number:** 5R01GM074728-16
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Aaron F Straight
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $331,390
- **Award type:** 5
- **Project period:** 2005-09-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10111522

## Citation

> US National Institutes of Health, RePORTER application 10111522, Mechanisms of Kinetochore Assembly (5R01GM074728-16). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10111522. Licensed CC0.

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