# Centromere Function and Dicentric Chromosome Stability

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $322,000

## Abstract

Chromosome inheritance ensures transmission of genetic and genomic information. Abnormal chromosome
number (aneuploidy) and altered chromosome structure cause birth defects, reproductive abnormalities, and
cancer. The centromere is the locus required for chromosome segregation and genome stability. Normal
chromosomes typically have only one centromere, but, genome rearrangements associated with birth defects and
cancer produce chromosomes in which two centromeres are physically linked. These dicentrics are not usually
tolerated in most model organisms, as originally illustrated in maize by Barbara McClintock nearly 80 years ago.
Paradoxically, dicentric chromosomes occur frequently in the general human population and are extremely
stable during cell division. A major impediment in studying dicentric chromosome formation and fate in humans
has been the absence of experimental systems. To circumvent this long-standing problem, we developed assays
to experimentally create dicentric human chromosomes that molecularly mirror those that occur naturally and
are biomedically relevant. We showed that in some of these de novo dicentrics, centromere inactivation occurred
by partial centromere deletion. However, many of our engineered dicentric chromosomes, particularly dicentric
X isochromosomes (dicXs), retain two active centromeres and are very stable. This finding appears to contradict
McClintock's model of dicentric fate. In this proposal, we will build on our previous studies of dicentric human
chromosomes by leveraging an inducible dicX assay system to explore molecular mechanisms governing stability
of dicXs that maintain two active centromeres. We will focus on three major areas of investigation: 1) defining
the molecular links between dicentric structure (i.e. inter-centromere distance) and centromere composition and
kinetochore architecture; 2) testing the roles of alpha satellite genomic structure and transcription in dicentric
stability, and 3) investigating mechanisms of centromere protein inheritance that result in varying centromere
configurations on dicXs. Our work will place specific genomic and epigenetics events on the timeline of dicentric
formation and stabilization by making use of a powerful chromosome engineering system that generates
dicentric chromosomes that precisely model those that occur frequently in humans. These studies will also be
critical for understanding dicentric formation and structure, refining long-established models of dicentric
stability, and providing new molecular insights into inheritance of centromere function in humans.

## Key facts

- **NIH application ID:** 10217196
- **Project number:** 5R01GM129263-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** BETH A SULLIVAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $322,000
- **Award type:** 5
- **Project period:** 2019-09-11 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217196

## Citation

> US National Institutes of Health, RePORTER application 10217196, Centromere Function and Dicentric Chromosome Stability (5R01GM129263-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10217196. Licensed CC0.

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