2- cdc4

2- cdc4 - REVIEWS RATCHETS AND CLOCKS THE CELL CYCLE...

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In 1983, rapidly dividing sea urchin embryos were dis- covered to express several proteins with high cell-cycle- correlated periodicity 1 .Furthermore, the periodicity of these proteins, which were accordingly termed ‘ CYCLINS ’, was shown to be the result of a constant synthetic rate coupled to a defined window of specific proteolysis at the end of the cell cycle 1 .Although many years passed before the function of cyclins as positive regulators of cell-cycle transitions was elucidated, those observations indicated that regulated proteolysis was likely to be important for cell-cycle control. In the ensuing years, that suggestion has been confirmed to an extent that was never initially anticipated. Indeed, much of cell- cycle control as it is understood at present directly depends on the targeted proteolysis of key cell-cycle regulators. At the time when the oscillations of cyclins were first being charted, the function of a 76-amino- acid polypeptide, UBIQUITIN , as a covalently attached marker for protein turnover was also coming to light 2 . Although the consequences of ubiquitin conjugation on protein half-life were clearly shown in the early to mid-1980s, and there were hints that protein instability was important for cell-cycle control even earlier 3,4 , the pervasiveness of ubiquitin-mediated protein turnover or its central role in cell-cycle control were not fully appreciated. Indeed, the first demonstration that a cell- cycle regulatory protein, cyclin B, was targeted for destruction by ubiquitylation was not published until 1991 (REF.5).The intended purpose of this review is not only to describe the current models of the cell cycle, integrating the roles of regulated proteolysis, but also to address the issue of why proteolysis has figured so prominently in the underlying mechanisms of cell-cycle control since the early days of eukaryotic evolution. Cell-cycle targets of ubiquitin-mediated proteolysis. Cell division is a complex and dangerous undertaking for a cell. In order to maintain genetic and functional integrity, cells must progress unidirectionally through a defined and highly regulated sequence of events that are known collectively as the cell cycle. The events of the cell cycle are organized roughly into ‘phases’: G1, S (in which chromosomal replication takes place), G2 and M (in which the components of the cell, including repli- cated chromosomes, are divided). The list of cell-cycle regulatory proteins that are targeted for turnover by ubiquitin-mediated proteolysis is extensive. Some note- worthy examples in yeast and mammalian cells are shown in FIG.1a and FIG.1b,respectively, and are listed in TABLE 1.These include, not surprisingly, cyclins, but also key negative regulators of cell-cycle transitions, as well as proteins that are engaged in a variety of cell-cycle functions. Generally, the targeted proteins fall into two general classes: first, those for which ubiquitin-medi- ated destruction is central to their proper function — for example, proteins that temporarily halt cell-cycle
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This note was uploaded on 05/26/2011 for the course BIO 445 taught by Professor Staff during the Spring '11 term at UNC.

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2- cdc4 - REVIEWS RATCHETS AND CLOCKS THE CELL CYCLE...

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