# Mechanisms of chromosome segregation, aneuploidy, and tumorigenesis

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $1,021,694

## Abstract

PROJECT SUMMARY
Chromosome missegregation or errors in cytokinesis produce aneuploidy, a chromosome content other than a
multiple of the haploid number. The linkage of aneuploidy to tumorigenesis has long been recognized. A striking
chromosomal abnormality linked to chromosome missegregation is chromothripsis (also known as
chromoanagenesis), an event in which one (or two) chromosomes appear to have been shattered into tens to
hundreds of small genomic fragments and religated back together in random order. Chromotriptic chromosomes
are now recognized to be present in a broad range of cancers.
With support from an NIGMS R35 grant, we have identified mechanisms of normal chromosome segregation
that act to prevent aneuploidy in the normal situation and have determined that single chromosome
missegregation or transient spindle pole amplification is a driver of tumorigenesis. We have identified the
epigenetic mark of centromere identity and determined that DNA replication acts as an error correction
mechanism to maintain that identity. We have identified key molecular mechanisms underlying the mitotic
checkpoint (also known as the spindle assembly checkpoint), the primary guard against chromosome
missegregation in mammals. We have identified how both mitotic checkpoint activation and silencing involve the
catalytic action of a conformation altering AAA+ ATPase TRIP13. We have also determined that mitotic exit has
an absolute requirement for TRIP13-mediated disassembly of the checkpoint inhibitor or the non-essential
APC15 subunit of the E3 ubiquitin ligase that targets mitotic cyclin destruction. By exploiting a unique feature of
the human Y centromere, we have produced cells in which we can induce selective, transient inactivation of the
Y centromere, with the Y chromosome missegregated into micronuclei at high frequency. With these and whole
genome sequencing, we determined that simple missegregation into a micronucleus can initiate chromothripsis
and drive the complex genome rearrangements frequently found in human cancer.
In the upcoming 5 years, we propose to determine mechanisms of fragmentation of a chromosome during
chromothripsis, identify and validate nucleases that fragment micronuclear chromosomes, determine how
shattered chromosomes are reassembled and produce extrachromosomal DNA (ecDNA), determine
mechanisms of inheritance of ecDNA, and determine the role of spatial proximity in the inheritance of centromere
identity, including neocentromere formation and other genomic abnormalities. We will also exploit our
development over the last 15 years of antisense oligonucleotide (ASO) therapy for nervous system disease to
undertake proof of principle therapy development targeting inactivation of the mitotic checkpoint by testing
suppression of TRIP13/APC15 for the major brain cancer glioblastoma.

## Key facts

- **NIH application ID:** 10674798
- **Project number:** 5R35GM122476-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Don W Cleveland
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,021,694
- **Award type:** 5
- **Project period:** 2017-05-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10674798

## Citation

> US National Institutes of Health, RePORTER application 10674798, Mechanisms of chromosome segregation, aneuploidy, and tumorigenesis (5R35GM122476-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10674798. Licensed CC0.

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