Polo kinase and cytokinesis initiation in mammalian cells: harnessing the awesome power of chemical genetics.

The last decade has brought rapid advances in our knowledge of the human genome, as well as increasingly sophisticated methods to analyze how each of approximately 30,000 genes within it contribute to cellular, tissue, and organismal function. Here, we review this technological revolution in the context of Polo-like kinase 1 (Plk1), which has emerged as a central regulator of multiple processes fundamental to cell division. In particular, we highlight similarities and differences when Plk1 function is probed through various methods, including novel chemical inhibitors, and how our understanding of Plk1's role in mitosis and cell division has been enhanced as a consequence.

Chemical genetics reveals the requirement for Polo-like kinase 1 activity in positioning RhoA and triggering cytokinesis in human cells.

Polo-like kinases (Plks) play crucial roles in mitosis and cell division. Whereas lower eukaryotes typically contain a single Plk, mammalian cells express several closely related but functionally distinct Plks. We describe here a chemical genetic system in which a single Plk family member, Plk1, can be inactivated with high selectivity and temporal resolution by using an allele-specific, small-molecule inhibitor, as well as the application of this system to dissect Plk1's role in cytokinesis.

Multiple roles for separase auto-cleavage during the G2/M transition.

The cysteine protease separase triggers anaphase onset by cleaving chromosome-bound cohesin. In humans, separase also cleaves itself at multiple sites, but the biological significance of this reaction has been elusive. Here we show that preventing separase auto-cleavage, via targeted mutagenesis of the endogenous hSeparase locus in somatic cells, interferes with entry into and progression through mitosis.