Molecular mechanisms underlying accurate chromosome segregation

Since Flemming introduced the term “mitosis” over 100 years ago, a challenge has been to understand how cells divide and faithfully transmit chromosomes at each cell division. Errors in the distribution of chromosomes during mitosis lead to the production of cells with an abnormal chromosome content, which in early development lead to lethal growth defects and may later contribute to the development of cancer. My laboratory studies the molecular mechanisms that control accurate chromosome distribution and the role that mitotic errors play in human health and disease. Our work utilizes a combination of chemical biology, biochemistry, cell biology and genetically engineered mice to study pathways involved in mitosis and their effect on cell and organism physiology. A major focus of the group is to develop cell and animal-based models to study the role of cell division defects in genome instability and tumorigenesis.

 

Centrosome biogenesis and copy number control

Centrosomes are major microtubule organizing centers that play an important role in mitosis where they organize the two poles of the bipolar microtubule spindle apparatus upon which chromosomes are segregated. At the beginning of the cycle, cells contain exactly one centrosome that duplicates once, and only once, before the next cell division, to ensure that cells possess only two centrosomes when they divide. The acquisition of more than two centrosomes leads to errors in spindle assembly that can give rise to aneuploid progeny. Moreover, cancer cells often have extra centrosomes that contribute to the genomic instability characteristic of this disease. Centrosomes and chromosomes are the only two structures in mammalian cells whose copy number is precisely controlled through a once per cell cycle duplication event and equal segregation into the daughter cells during mitosis. We are interested in dissecting the molecular mechanisms that allow the creation of a single centrosome per cell cycle and determining role that supernumerary centrosomes play in the development of cancer.

 

Featured Research

Centrosomes are major microtubule organizing centers that play an important role in organizing the two poles of the bipolar microtubule spindle apparatus upon which chromosomes are segregated. Centrosomes are one of only two structures in mammalian cells whose copy number is precisely controlled (the other structure is the chromosome). At the beginning of the cycle, cells contain exactly one centrosome that duplicates once, and only once, before the next cell division to ensure that cells...

Conditional inactivation or depletion of proteins is a powerful method for determining gene function and central to our understanding of complex biological systems. Protein expression is frequently controlled at the DNA level by disruption of the coding sequence of the gene or at the level of the mRNA by employing methodologies for suppressing mRNA accumulation, especially with RNA interference (RNAi). However, in both cases protein depletion is indirect and the rapidity of loss is dependent on the stability of the protein, resulting in very slow loss for long-lived proteins. This serves...

Movements of chromosomes during mitosis are achieved by their attachment to the bipolar mitotic spindle, whose assembly is initiated from a pair of spindle poles. Chromosomes attach to the microtubule spindle at proteinaceous structures known as kinetochores. A long-standing question in the field is: how is chromosome movement on the mitotic spindle coordinated?

 

During my postdoctoral work we demonstrated that chromosome motion and stable microtubule capture is controlled by the sequential action of Aurora kinase and Protein phosphatase-1 (PP1) on the kinetochore motor...

A wealth of correlative evidence points to a role of centrosome amplification in the development of a wide array of cancer. However a direct test of this hypothesis has yet to be achieved in a vertebrate system due to difficulties in generating centrosome amplification in the absence of direct effects on oncogenes, tumor suppressor genes or cellular ploidy. Plk4’s only known function is in regulating centrosome copy number and therefore, increasing Plk4 levels provides a mechanism to create supernumerary centrosomes in vivo in the absence of additional defects. Moreover,...