# Mechanisms of Acentric Chromosome Transmission

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA CRUZ · 2020 · $336,387

## Abstract

PROJECT SUMMARY
 In spite of sophisticated checkpoints, repair mechanisms and other safeguards, cells
occasionally enter and exit metaphase with damaged DNA. While much is known about the response of
the cell to DNA damage during interphase, the response of a cell entering and exiting metaphase with
damaged DNA is largely unexplored. Of particular interest is the consequence of entering and exiting
metaphase with unrepaired double-strand breaks (DSB). DSB's are especially troublesome, because
they produce chromosome fragments lacking telomeres, as well as fragments lacking centromeres
(acentrics). Although acentrics chromosome fragments were described over a century ago and are a
common feature of cancer cells, surprisingly little is known about their behavior and fate during mitosis,
largely because it has been difficult to generate acentrics that can be analyzed in living cells. To directly
address this issue, my lab has developed a system in Drosophila neuroblasts to efficiently generate
DSBs at a single defined region at the base of the X chromosome (through induction of I-CreI
endonuclease) and follow the behavior of the resulting acentric fragment through high resolution live
microscopy. These studies reveal that in spite of lacking a kinetochore, acentrics exhibit highly delayed,
but ultimately successful congression, sister chromosome separation, anaphase poleward segregation
and incorporation into daughter telophase nuclei. We also discovered that the late segregating
acentrics are accompanied by a series of cellular adaptations that facilitate its segregation and inclusion
in daughter nuclei. These include an increase in cell and spindle length, expansion of the cytokinetic
contractile apparatus, and delayed in initiation and completion of nuclear envelope reformation at
telophase. We view congression and segregation of acentric chromosomes into telophase daughter
nuclei as a mechanism of last resort for maintaining genomic integrity when the eukaryotic cell enters
anaphase with unrepaired DSBs. Our goal is to identify structural and regulatory mechanisms driving
acentric segregation and the accompanying cellular adaptations. To achieve this, we propose three
specific aims to define the mechanisms that mediate: 1) acentric sister chromatid congression, 2)
poleward segregation of the acentrics, 3) the cellular adaptations to the presence of an acentric during
anaphase/telophase. It is anticipated that these studies will reveal unsuspected novel mechanisms
operating during anaphase and telophase that maintain the integrity of the eukaryotic genome.

## Key facts

- **NIH application ID:** 9968414
- **Project number:** 5R01GM120321-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA CRUZ
- **Principal Investigator:** William T. SULLIVAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $336,387
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968414

## Citation

> US National Institutes of Health, RePORTER application 9968414, Mechanisms of Acentric Chromosome Transmission (5R01GM120321-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9968414. Licensed CC0.

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