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Dissecting centromeric DNA-microtubule interactions In vitro uncovers a mechanism that ensures proper connection of chromosomes to the mitotic spindle


Mitosis is the period of the cell cycle during which the duplicated genome is equally partitioned into two daughter cells. Cells accomplish this feat by condensing their chromosomes into compact units that are aligned and segregated by the cytoskeleton. This process requires correct attachment of sister chromatids to the dynamic mitotic spindle. Attachment errors have severe consequences and can lead to developmental defects, cell death, and cancer. The molecular machine responsible for making attachments between chromosomes and the mitotic spindle is the kinetochore. Composed of over 60 proteins, the kinetochore serves as the attachment interface between chromosomes and microtubules and monitors its' own attachment status. The coupling of these two functions provides a mechanism to delay cell division until all sister chromatids are properly attached to the mitotic spindle, ensuring their correct segregation. While the functions of the kinetochore have long been appreciated, the underlying molecular mechanisms have remained elusive. Studies presented here, which utilize the biochemical and genetic amenability of budding yeast, Saccharomyces cerevisiae, reveal a specific attachment between the centromeric DNA and microtubules that is mediated by two conserved proteins Bir1/Survivin, and Sli15/INCENP. These proteins are of particular interest for their multiple roles in cell division and their potential use as cancer therapy targets since both are over-expressed in several types of cancer. The Bir1/Survivin-Sli15/INCENP mediated attachment is not responsible for making "core attachments" between kinetochores and microtubules, but instead functions to regulate the conserved kinase, Ipl1/ Aurora B. Ipl1/Aurora B, Sli15/INCENP, and Bir1/Survivin are known collectively as the chromosomal passenger complex (CPC) and over a decade of work has revealed that they are important for regulating kinetochore attachments, presumably by recognizing the amount of tension felt by sister chromatids when they are correctly attached to the mitotic spindle. The discoveries described in Chapter 2 has led to the hypothesis that this Bir1/Survivin-Sli15/ INCENP mediated attachment is sensing tension directly to regulate Ipl1/Aurora B, which in turn regulates attachments. This model forms the basis for work presented in Chapter 3, which explores the molecular mechanisms of how the Bir1/Survivin-Sli15/INCENP mediated CEN-DNA linkage regulates and is regulated by Ipl1/Aurora B

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