Cell Cycle Checkpoint Control

Checkpoints are regulatory mechanisms that control the timing of transitions between cell cycle phases. Each checkpoint is regulated by a signal transduction cascade that can trigger cell cycle arrest in the presence of cellular damage. The best characterized checkpoints detect incorrect DNA structures, including physically damaged DNA, incompletely replicated DNA, or improperly formed mitotic spindles. Many of the components of these signal transduction cascades have been conserved throughout eukaryotic evolution, as similar genes have been found to regulate these processes in yeast and man. A number of genes that regulate checkpoints act as tumour suppressors in humans, including p53 and BRCA1.

Ongoing work involves characterization of the human G2 checkpoint control genes, including Rad9A, Tlk1, Chk1 and BRCA1.  The lab was involved in the identification of Rad9A, as well as for demonstrating its role in the 9-1-1 checkpoint complex.  Structure-function studies have identified the roles of a complex series of phosphorylations on Rad9A.  Recent studies have identified a positive feeback mechamism that supports checkpoint signal after DNA damage.  Current work is aimed at characterizing the molecular mechanisms regulating this feedback loop.