Work in the Rudner lab is focused on understanding fundamental problems of chromosome dynamics. Defects in chromosome structure and segregation can lead to chromosome loss and damage, both critical events in the development of cancer and chromosomal disorders. We use the budding yeast, Saccharomyces cerevisae, as a model for understanding the assembly and regulation of chromosomes. Budding yeast is an excellent model system because most cell biology is well conserved between yeast and humans, and yeast provides a facile genetic system in which hypotheses can be rapidly and rigorously tested.
The Rudner lab accepts students from graduate programs in Biochemistry.
Our work studying chromosome segregation is focused on understanding how cells know when to initiate anaphase. At anaphase onset, replicated sister chromatids segregate into two daughter cells. Errors in this highly orchestrated event can cause loss, gain and damage to chromosomes. Changes in chromosome content (also called aneuploidy) are very problematic for cells and are found in almost all cancers. Anaphase onset requires the activity of Cdk1 (Cyclin-dependent kinase) a highly conserved protein kinase, and our work has focused on how upstream regulators of Cdk1 regulate anaphase initiation, elucidating the critical targets of Cdk1 that trigger anaphase and understanding how protein phosphatase 2A (PP2A) counteracts Cdk1 activity. Understanding the fundamental mechanisms of how cells trigger anaphase will help lead to therapeutics that improve the fidelity of chromosome segregation as well as new anti-mitotic chemotherapeutics.
We are also interested in understanding how particular chromosomal domains assemble, specifically heterochromatin. Heterochromatin, or silent chromatin, which constitutes up to half of the vertebrate genome, is remarkably dynamic: it is epigenetically inherited and its boundaries and locations change as cells divide and differentiate. Budding yeast heterochromatin is assembled from the the Sir2, Sir3 and Sir4 proteins bound to nucleosomal DNA. We have been focused on understanding how heterochromatin is regulated during the cell cycle, distinguishing the role of the Sir proteins in nucleation and spreading of heterochromatin, determining the structural basis of heterochromatin spreading and understanding what aspects of Sir-dependent silencing is conserved in vertebrates.
A new project in the laboratory is the result of a fruitful collaboration between our lab and Pranesh Chakraborty and Martin Holcik, researchers at the Children’s Hospital of Eastern Ontario (CHEO). They have recently identified a cohort of children with SIFD (sideroblastic anemia with B cell immunodeficiency, periodic fevers and developmental delay), a new congenital disorder that resembles other inherited mitochondrial diseases. Whole exome sequencing of these patients has shown that a highly conserved translation factor is mutated in these patients. We are currently using yeast to examine why mutations in this gene cause disease.