Dr. Sue Biggins

Regulation of chromosome segregation.

How do cells faithfully inherit a complete set of chromosomes during every cell division? My laboratory is focused on elucidating the mechanisms that govern chromosome segregation. Because aneuploidy is a hallmark of all cancers and many birth defects, studies on chromosome segregation are critical to understanding how cells maintain genomic stability and prevent disease. Chromosomes segregate using their kinetochores, the specialized protein structures that are assembled on centromeric DNA sequences and attach to dynamic spindle microtubules. Sister kinetochores must make bioriented attachments to microtubules from opposite poles. Defects in making bioriented kinetochore attachments are detected by the spindle checkpoint that halts the cell cycle until the errors are corrected. My lab is studying many key questions about chromosome segregation, including how kinetochores assemble, how kinetochores make bioriented microtubule attachments, and how the spindle checkpoint detects and corrects defects in these processes.

One of our interests is a key regulator of chromosome segregation in all eukaryotes, the Ipl1/Aurora protein kinase. Because the Aurora kinases are oncogenes, studies on the budding yeast Ipl1 protein are critical to understanding both chromosome segregation and the maintenance of genomic stability. We previously found that Ipl1 leads to the detachment of kinetochores that are not bioriented, giving the cell another chance to make proper bioriented attachments to kinetochores. We are also studying the opposing phosphatase, Glc7, and have recently found that it silences the spindle checkpoint. Current projects in the lab are directed at identifying key substrates for Ipl1 and Glc7 as well as understanding the precise temporal and spatial regulation of the enzymes.

We are also studying the specialized centromeric chromatin structure that is critical for kinetochore assembly and function. All eukaryotic kinetochores contain a centromeric histone H3 variant (CenH3) that forms a specialized centromeric nucleosome and appears to be the epigenetic mark that specifies the site of kinetochore assembly. We previously discovered that CenH3 is regulated by ubiquitin-mediated proteolysis to restrict CenH3 localization to kinetochores. We have recently identified a ubiquitin ligase that degrades CenH3 that mislocalizes to euchromatin and are currently studying its regulation. We also have a number of projects studying histone modifications that are important for centromeric function.

We have recently developed a method to purify the kinetochore and are using this for a number of structural, biophysical and biochemical studies of kinetochores. In collaboration with Chip Asbury's lab, we are performing biophysical experiments to understand how kinetochores maintain load bearing attachments to dynamic microtubules. We are also collaborating with Tamir Gonen to elucidate structural details about kinetochores and their mode of attachment to microtubules. Finally, we are using this assay to identifiy novel post-translational modifications on kinetochores and to reconstitute the spindle checkpoint in vitro. Taken together, these studies should continue to elucidate new details about the mechanisms of chromosome segregation and thus aid in understanding the generation of aneuploidy and disease progression.