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Principal Investigator: William T. SULLIVAN
Organization: UNIVERSITY OF CALIFORNIA SANTA CRUZ
Fiscal Year: 2024
Award: $375,913
Funding agency: National Institute of General Medical Sciences
The goal of this proposal is to elucidate the molecular and cellular basis of a newly discovered diverse
set of adaptive mechanisms that maintain the integrity of the genome during anaphase and telophase.
Eukaryotic cells have evolved sophisticated mechanisms to maintain genomic integrity. In response to insults
to the genome, checkpoints delay progression through the cell cycle, providing time for either repair of the
damaged DNA or induction of apoptosis to eliminate the compromised cell. The majority of previous studies have
focused on checkpoint mechanisms operating during interphase and metaphase. In spite of these safeguards,
cells occasionally enter and progress through metaphase with damaged DNA, lagging chromatin, or a
chromosome which has failed to secure a stable association with a kinetochore microtubule. Focusing on these
errors led to the discovery of the abscission checkpoint, which delays the final stages of cytokinesis, providing
time to clear chromatin from the path of the cytokinesis furrow. This discovery changed the prevailing view that,
once the spindle-assembly checkpoint is satisfied, anaphase and telophase proceed rapidly without error
correction mechanisms. Clearly, this is not the case and a number of labs, included ours, investigate the
compensatory mechanisms that operate during anaphase to maintain genomic integrity. Here, we propose that
in addition to the abscission checkpoint, the eukaryotic cell maintains a sophisticated and diverse set of
mechanisms that function during the anaphase-telophase transition to ensure that chromosome fragments
lacking a kinetochore (acentrics) are successfully transmitted and incorporated into daughter nuclei. This
conclusion is based on our finding that in Drosophila, acentric chromosome fragments successfully congress,
undergo delayed but proper sister separation, and efficiently segregate to opposing poles and incorporate into
daughter nuclei. This was surprising as all of these chromosome dynamics were thought to be largely driven by
kinetochore-microtubule associations. Our studies revealed a number of previously undescribed mechanisms
and cellular adaptations such as DNA tethers, cell and spindle elongation, and channels in the nuclear envelope.
We view these as revealing novel mechanisms operating during anaphase/telophase to maintain genomic
integrity. In addition, observing the behavior of acentric chromosome fragments reveals forces acting on
chromosomes that are independent of the kinetochore-microtubule attachments. We view these as key
mechanisms that maintain genomic fidelity when cells exit metaphase with damaged chromosomes. Given that
transmission of acentric chromosomes and DNA bridges have been observed across the phyla, many of these
mechanisms are likely conserved. The studies described here rely on a combination of genetic, fluorescent and
electron microscope studies as well as on high throughput cell-based screens to determine the molecular basis
of these adaptive mechanisms functioning at the final stages of the eukaryotic cell cycle.
Terms: <Abscission><Anaphase><Behavior><Cancers><Cell Body><Cell Cycle><Cell Division Cycle><Cell Nucleus><Cell division><Cells><Chromatin><Chromosomes><Congresses><Cytokinesis><Cytoplasmic Division><DNA><DNA Damage><DNA Damage Repair><DNA Injury><DNA Repair><Daughter><Deoxyribonucleic Acid><Disease><Disorder><Drosophila><Drosophila genus><Electron Microscope><Ensure><Eukaryotic Cell><Excision><Extirpation><Genetic><Genome><Genomics><Goals><Grant><Induction of Apoptosis><Interphase><Kinetochores><Malignant Neoplasms><Malignant Tumor><Metaphase><Micro-tubule><Microtubules><Mitotic><Mitotic Anaphase><Mitotic Metaphase><Molecular><Nuclear Envelope><Nuclear Membrane><Nucleus><Removal><Secure><Sister><Surgical Removal><Time><Transmission><UV laboratory microscope><Ultraviolet Microscopes><Unscheduled DNA Synthesis><chromosome replication><daughter cell><fluorescence microscope><fluorescence/UV microscope><fluorescent microscope><fruit fly><genome integrity><genomic integrity><laboratory fluorescence light microscope><malignancy><neoplasm/cancer><novel><resection><response><segregation><telophase><transmission process>