In animal cells, nuclear structure is completely dismantled during the process of mitosis. Although chromosomes are concomitantly remodeled into compact, protective structures, various sources of error can put genome stability at risk at this time of cell division. Chromosome division itself can be a time of genome destabilizing errors, if the spindle assembly checkpoint fails to ensure that chromosome alignment is complete prior to their segregation. In some cases, events in the previous cell cycle, such as incomplete DNA replication, put the genome in jeopardy at mitosis. In other cases, mis-coordination of events in late mitosis gives rise to DNA damage. Events downstream of these potential errors thus play an integral role in maintaining genome stability. A growing body of knowledge about the rapid steps of nuclear assembly and an appreciation for the importance of genome surveillance in newly-formed nuclei provide a foundation for the proposed research designed to address how cells cope with mitotic errors. The research proposed is centered on conceptually innovative hypotheses and seeks to make novel inroads into the inter-connections between nuclear assembly, genome surveillance, and cytokinesis. Building on the new observation that the nuclear envelope at lagging chromosomes has a specific set of constituent proteins, our first aim is to define how the nuclear envelope differs at mis-segregated chromosomes, testing the hypothesis that these changes alter membrane sealing. The impact that this distinctive nuclear envelope domain has on nuclear integrity and the frequency with which mis- segregating chromosomes re-integrate into the nucleus will be determined by live-imaging. We will also interrogate the role of the kinase Aurora B in regulating regional differences at the NE of lagging chromosomes. In cases where the lagging chromosome separates from the main nucleus, our results will also lend insight into why resulting micronuclei have attributes that escalate DNA damage and instigate innate immune signaling.
The second aim i s focused on mechanisms involved in genome surveillance after mitosis. To gain unique perspective on this process, we will pursue the roles of Nup153 and Nup50 in targeting the DNA damage response factor 53BP1 to surveillance foci. Finally, we will determine what activates the abscission checkpoint, a regulatory event downstream of mitosis that halts the final step of cell division. Having observed a robust connection between loss of Nup153 function and the abscission checkpoint, we hypothesize that this is due to the dual roles of Nup153 in nuclear formation and genomic surveillance. More broadly, we will test the hypothesis prompted by this paradigm: that loss of nuclear integrity --and the damage to DNA that ensues-- are monitored by the abscission checkpoint and become a particularly potent signal when genome surveillance mechanisms are compromised. The results obtained will bring significant new insight into diverse mechanisms that preserve genome integrity and contribute to an integrated understanding of fundamental cell cycle regulatory mechanisms.

Public Health Relevance

The overarching goal of this research is to understand mechanisms that preserve the integrity of DNA inherited by each daughter cell during division. We will take a multi-disciplinary approach to understand how nuclear envelope formation differs at mis-segregated chromosomes, how nuclear pore proteins promote genome surveillance, and how these processes inform the decision to separate daughter cells. The knowledge gained will help us decipher how these mechanisms support genomic stability in highly proliferative organs, such as skin, intestine, and blood, as well as how they go awry in cancer.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
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Gindhart, Joseph G
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University of Utah
Internal Medicine/Medicine
Schools of Medicine
Salt Lake City
United States
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