are degraded in a ubiquitin-independent manner. The most well-known example of a ubiquitin-independent proteasome substrate is the enzyme ornithine decarboxylase. Ubiquitin-independent mechanisms targeting key cell cycle regulators such as p53 have also been reported, although p53 is also subject to ubiquitin-dependent degradation. Finally, structurally abnormal, misfolded, or highly oxidized proteins are also subject to ubiquitin-independent and 19S-independent degradation under conditions of cellular stress. Evolution The 20S proteasome is both ubiquitous and essential in eukaryotes and archaea. The bacterial order Actinomycetales, also share homologs of the 20S proteasome, whereas most bacteria possess heat shock genes hslV and hslU, whose gene products are a multimeric protease arranged in a two-layered ring and an ATPase. The hslV protein has been hypothesized to resemble the likely ancestor of the 20S proteasome. In general, HslV is not essential in bacteria, and not all bacteria possess it, whereas some protists possess both the 20S and the hslV systems. Many bacteria also possess other homologs of the proteasome and an associated ATPase, most notably ClpP and ClpX. This redundancy explains why the HslUV system is not essential. Sequence analysis suggests that the catalytic β subunits diverged earlier in evolution than the predominantly structural α subunits. In bacteria that express a 20S proteasome, the β subunits have high sequence identity to archaeal and eukaryotic β subunits, whereas the α sequence identity is much lower. The presence of 20S proteasomes in bacteria may result from lateral gene transfer, while the diversification of subunits among eukaryotes is ascribed to multiple gene duplication events. Cell cycle control Cell cycle progression is controlled by ordered action of cyclin-dependent kinases (CDKs), activated by specific cyclins that demarcate phases of the cell cycle. Mitotic cyclins, which persist in the cell for only a few minutes, have one of the shortest life spans of all intracellular proteins. After a CDK-cyclin complex has performed its function, the associated cyclin is polyubiquitinated and destroyed by the proteasome, which provides directionality for the cell cycle. In particular, exit from mitosis requires the proteasome-dependent dissociation of the regulatory component cyclin B from the mitosis promoting factor complex. In vertebrate cells, "slippage" through the mitotic checkpoint leading to premature M phase exit can occur despite the delay of this exit by the spindle checkpoint. Earlier cell cycle checkpoints such as post-restriction point check between G1 phase and S phase similarly involve proteasomal degradation of cyclin A, whose ubiquitination is promoted