PROTEIN DEGRADATION BY THE ANAPHASE PROMOTING COMPLEX IN SPACE AND TIME -A role for the intrinsic characteristics of the substrates-
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In order to create two new daughter cells out of one mother cell, a cell has to duplicate genetic information through DNA replication during S-phase and divide this DNA equally into the two new daughter cells during mitosis. The importance of proper regulation of cell divison is f underscored by the fact that misregulation can lead to various developmental problems and diseases and is involved in all cases of tumor formation. Ordered progression through the cell cycle dependent on the levels and activity of a large variety of proteins. Accurate protein regulation not only requires the up regulation at specific time points, degradation at the end of a specific phase is sometimes even more important. One of the most important regulators of protein degradation is the anaphase promoting complex (APC/C). The APC/C is a multi-subunit E3 ubiquitin ligase which performs its various functions by assembling poly-ubiquitin chains on substrate proteins. Since the identification of the APC/C, only fifteen years ago, extensive research in the cell cycle and protein degradation field has elucidated more and more about its structure, functions, downstream targets and regulatory mechanisms. The final substrate degradation however is not only dependent on the activity of the APC/C but also on the intrinsic characteristics of the substrates. Therefore, understanding the differences between these substrates might give novel insight in how these substrates ensure their own degradation and how they, next to the regulatory mechanisms controlling the APC/C, contribute to a temporal ordered sequence of protein degradation. Here several mechanisms regulating APC/C activity and models describing the role of substrates in their own degradation will be discussed in order to better understand their role in targeting proteins to the proteasome at the right time during the cell cycle.