Kitagawa K: Molecular mechanisms of high-fidelity chromosome transmission



A fundamental requirement of the cell division cycle is the maintenance, replication, and segregation of chromosomal DNA, the specific order of which is ensured by checkpoints. Our research focuses on the molecular mechanisms of high-fidelity chromosome transmission and the regulatory mechanisms that ensure proper execution of the cell cycle. Genome stability is vital to maintain human health. Failure of the complex mechanisms involved in maintaining genome integrity has been implicated in cancer, aging, and congenital birth defects. Despite these findings, the molecular basis of genome instability in human disease is largely unknown.

We have used Saccharomyces cerevisiae as a model system to study by an interdisciplinary approach the molecular and regulatory mechanisms of chromosome transmission. The conservation of basic cellular mechanisms in eukaryotes and the identification of functional and structural human homologs of yeast genes allow our findings in yeast to be extrapolated to humans. Studies on chromosome segregation and cell cycle regulatory processes in S. cerevisiae and their corresponding human homologs will help us understand the molecular basis of tumorigenesis. Mutations in genes required for kinetochore function and mitotic checkpoint surveillance possibly contribute development of cancer. Recent phenotypic and mutational analyses of colon tumors strongly suggest that the integrity of the mitotic spindle checkpoint pathway is a major determinant in tumorigenesis. The mitotic checkpoint mechanism responds to defects in the chromosome segregation machinery and arrests cells in mitosis prior to anaphase (Fig.1). The kinetochore plays a key role in this process and is also the site for many checkpoint proteins.


Fig 1. The kinetochore, the spindle checkpoint, and the anaphase-promoting complex (APC).

Improper kinetochore–microtubule attachment is thought to send a signal to the spindle checkpoint, which consists of Bub and Mad proteins, to protect cells from chromosome missegregation caused by mitotic errors. When the checkpoint is activated, it stops the cell cycle by inhibiting the anaphase-promoting complex (APC, also called cyclosome), a ubiquitin-dependent proteolysis complex. APC inhibition causes the accumulation of securin, which in turn inhibits separase activity, which targets cohesion proteins. As a result, cohesion is maintained and sister chromatids remain bound together, which arrests cells in mitosis and thereby prevents aneuploidy. Defects in the mitotic spindle checkpoint result in subsequent cell death or aneuploidy, which might contribute to tumorigenesis.


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