UC San Diego

Faithful segregation of genetic material during mitosis is a vital cellular function that ensures the accurate passage of critical information from one generation to the next. Errors in this process can be highly deleterious, often times leading to aneuploidy- a hallmark of cancer and the leading genetic cause of birth defects and miscarriages. Given the potentially harmful nature of cells resulting from defects in mitosis, a majority of these cells are eliminated via apoptosis to prevent further propagation of this damage. However, this is not always the case as sometimes these cells evade cell death and continue to proliferate. Although the link between mitotic defects and activation of the cell death machinery is relatively well established, the underlying mechanism still remains unclear. The work presented here takes a closer look, in both the model system Caenorhabditis elegans and human tissue culture cells, at the direct effect of a variety of mitotic perturbations in an effort to better understand how mitotic defects can signal to cell death. In the adult C. elegans germline, which is composed of both mitotic and meiotic cells, nuclei that result from a failed mitosis acquire an excess amount of double-strand breaks, activate the DNA damage checkpoint and are unable to successfully complete meiotic recombination. These nuclei are preferentially eliminated by apoptosis, a response that is dependent on the initiation of recombination, suggesting that the deliberate double strand breaks that are required for recombination survey and mark for elimination nuclei with the improper complement of chromosomes. In human tissue culture cells, perturbations that prevent proper exit from mitosis while allowing for perfect, or near perfect, alignment of chromosomes result in a distinct phenotype called chromosome scattering. Cells with scattered chromosomes show uncoordinated loss of chromatid cohesion and subsequent spindle defects, yet still maintain the hallmarks of an active mitosis. Most notably, cells with scattered chromosomes show an increased susceptibility to apoptosis. Overall the results of these studies reveal two distinct mechanisms by which mitotic defects signal to cell death helping to shed light on the driving force behind this phenomenon