Structure and function of the APC

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DESCRIPTION (provided by applicant): Progress through the cell cycle is controlled by the periodic synthesis and degradation of a large number of regulatory proteins. Cell cycle regulated degradation of proteins is accomplished by modifying proteins with ubiquitin, which then targets those proteins to the proteosome. Addition of ubiquitin is carried out by a class of enzymes called ubiquitin ligases. One of the most important ubiquitin ligases regulating cell cycle progression is called the anaphase promoting complex (APC). While many ubiquitin ligases are monomeric enzymes, the APC is a complex of 13 subunits, almost all of which are conserved in all eukaryotes. In addition to this core, catalytic complex, the APC associates with either of two specificity factors, called Cdc20 and Cdhl. These proteins are thought to mediate the APC's interaction with its substrates. Loss of any essential APC subunit results in a cell-cycle arrest in metaphase. Remarkably, any of the normally essential APC genes can be deleted if two important APC targets are deleted/inhibited: securin (Pds l) and the B-type cyclin/CDK complex. In addition to providing valuable information about the function of the APC in cell division, this work has also generated a novel tool for studying the enzymology and regulation of the APC. In this strain, we are able to modify the APC complex in ways that would be lethal in a wild type background. This proposal outlines strategies for using our APC-independent strains to analyze the function of the APC in cell cycle progression and the mechanisms by which it works.