# Cell Division Errors as a Mechanism Driving Massive Genomic Rearrangements

> **NIH NIH R00** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $249,000

## Abstract

PROJECT SUMMARY/ABSTRACT (DESCRIPTION)
Advances in DNA sequencing technologies have uncovered remarkable structural complexities within the
human cancer genome, including a new category of massive and localized intra-chromosomal rearrangements
coined chromothripsis. Since its discovery in 2011, the signatures of chromothripsis have now been detected in
a broad spectrum of solid and hematological tumors. These alterations are thought to occur during a single
catastrophic event; however, their underlying mechanistic origins are not well understood. Errors in mitotic cell
division can provoke chromothripsis through entrapment of missegregated chromosomes into aberrant
structures called micronuclei. Dr. Ly previously identified that chromosomes in micronuclei are subjected to
extensive shattering in mitosis, and the resulting DNA fragments are reassembled by canonical end-joining
repair in the subsequent interphase. This proposal for an NIH Pathway to Independence Award seeks to
understand how chromosome segregation errors during mitosis initiate a cascade of downstream genomic
instability events to directly shape or contribute to the cancer genome. In the first aim, examples of fully
functional chromosomes with de novo chromothripsis will be generated through development of a powerful and
reversible centromere-specific inactivation approach coupled to a chromosome-specific selection strategy in
human tissue culture cells. Genome-wide sequencing will be used to identify the hallmark features of
chromothripsis from unique clonal derivatives following chromosome missegregation into micronuclei. In the
second aim, the precise mechanisms and spatiotemporal dynamics of chromosome shattering and reassembly
events will be explored through multidisciplinary cell biological approaches, including gene disruption and live-
cell imaging. The third aim will focus on how chromosomes with gross rearrangements that lack a functional
alphoid centromere are able to propagate indefinitely through the epigenetic formation of a stable, new
centromere at non-alphoid loci. By leveraging his expertise in engineering sophisticated tissue culture models
combined with his background in cancer biology, these collective efforts by Dr. Ly will establish the
mechanisms and consequences of mitotic errors in triggering genomic instability – insights that are critical for
understanding the biogenesis of complex genomic features commonly manifested in patient tumors. During the
mentored K99 phase of the Award, Dr. Ly will receive additional and needed training at the Ludwig Institute for
Cancer Research under the guidance of Dr. Don Cleveland – a widely recognized and established leader in
the fields of cell division and aneuploidy. The Ludwig Institute for Cancer Research, the University of California
at San Diego, and the surrounding La Jolla scientific community serves as an exceptional atmosphere for
research training, collaborative science, and career development. An excellent te...

## Key facts

- **NIH application ID:** 10104453
- **Project number:** 5R00CA218871-05
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Peter Ly
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104453

## Citation

> US National Institutes of Health, RePORTER application 10104453, Cell Division Errors as a Mechanism Driving Massive Genomic Rearrangements (5R00CA218871-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10104453. Licensed CC0.

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