Genetics, Epigenetics & Gene Regulation | Molecular Cell Biology
Mechanisms that ensure chromosome segregation fidelity in mitosis
In mitosis, chromosome segregation by the microtubule-based mitotic spindle ensures equal partitioning of the genome between the daughter cell. Cells use multiple mechanisms to ensure that chromosomes are segregated with high fidelity. The vast majority of cancer cells are aneuploid (contain the wrong number of chromosomes), indicating that one or more of these segregation fidelity mechanisms has failed. The resulting increase in chromosome segregation errors is termed...more
In mitosis, chromosome segregation by the microtubule-based mitotic spindle ensures equal partitioning of the genome between the daughter cell. Cells use multiple mechanisms to ensure that chromosomes are segregated with high fidelity. The vast majority of cancer cells are aneuploid (contain the wrong number of chromosomes), indicating that one or more of these segregation fidelity mechanisms has failed. The resulting increase in chromosome segregation errors is termed chromosomal instability (CIN). Despite major recent advances in the genomic characterization of cancer cells, very little is known about how and why cancer cells missegregate their chromosomes.
We are interested in understanding the mechanisms that cells use to prevent the missegregation of chromosomes as well as the direct repercussions of chromosome missegregation. Our focus lies in fundamental, conserved processes that identify chromosomes with aberrant attachments to the microtubules and correct those misattachments. To examine these processes, we employ a combination of genetic, biochemical, and microscopy-based techniques using budding yeast as a model organism.
Aneuploid cancer cell lines have defects in the strength of attachments between microtubules and the kinetochore (the microtubule-attachment site on chromosomes), and the strength of these attachments is regulated by the kinase Aurora B. Aurora B provides the catalytic activity of the chromosomal passenger complex (CPC). The CPC is a four-subunit complex that detects improper microtubule-kinetochore connections and weakens them via phosphorylation of various targets on the kinetochore. One fundamental question that we wish to address is: how does the CPC specifically destabilize aberrant kinetochore-microtubule connections?
Many cancers have extremely high rates of chromosomal instability (CIN). Some cancers have chromosome segregation errors in every cell division, which would be detrimental to the growth of normal cells. Little is known about how cancers are able to thrive with high levels of CIN. We aim to determine how cells evolve to cope with CIN by creating a model system for persistent chromosomal instability in budding yeast. What types of mutations allow cells to adapt to a constantly shifting genomic content? What are the direct effects of CIN and aneuploidy on the health and viability of cells?
Campbell, Christopher S; Hombauer, Hans; Srivatsan, Anjana; Bowen, Nikki; Gries, Kerstin; Desai, Arshad; Putnam, Christopher D; Kolodner, Richard D (2014). Mlh2 is an accessory factor for DNA mismatch repair in Saccharomyces cerevisiae. PLOS GENET;10(5):e1004327. PMID: 24811092
Campbell, Christopher S; Desai, Arshad (2013). Tension sensing by Aurora B kinase is independent of survivin-based centromere localization. NATURE;497(7447):118-21. PMID: 23604256
Hombauer, Hans; Campbell, Christopher S; Smith, Catherine E; Desai, Arshad; Kolodner, Richard D (2011). Visualization of eukaryotic DNA mismatch repair reveals distinct recognition and repair intermediates. CELL;147(5):1040-53. PMID: 22118461
WWTF - Vienna Science and Technology Fund
The Campbell Group is supported through the "Vienna Research Groups for Young Investigators" program.
Doctoral Program "Chromosome Dynamics"
The Campbell group participates in in the special Doctoral Program 'Chromosome Dynamics' reviewed and funded by the Austrian Research Fund FWF.