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Control of the centriole and centrosome cycles by ubiquitination enzymes

Oncogene volume 21, pages 6209–6221 (2002)Cite this article

The role of the centriole in organizing the cell's cytoskeleton and its mechanism of duplication have been long-standing puzzles for cell biologists. Whereas the semi-conservative replication of chromosomes was established by Meselson and Stahl (1958), the likely parallels for semi-conservative duplication of the centrioles remain fuzzy. Further considering this parallel, molecular studies of chromosomal replication have begun to uncover how cell cycle regulators including cyclin-dependent kinases and ubiquitin ligases ensure that chromosomes replicate once-and-only-once per cell cycle (Blow and Hodgson, 2002; Dutta and Bell, 1997). The obvious need to maintain accurate control of centrosome number and thereby ensure spindle bipolarity would suggest that a similar once-and-only once control restricts the centrosome cycle.

Studies over the last decade on the budding and fission yeast spindle pole bodies (SPB) and the animal cell centrosome have defined a growing parts list of conserved components, as well as those specific to fungi or animals. The functional connection between the centrosome duplication cycle and the regulatory mechanisms controlling the chromosome duplication cycle suggested that semi-conservative replication for both centrosomes and chromosomes might be linked by these global timing mechanisms. In 1999, a series of studies demonstrated that cyclin-dependent kinases and both the SCF and APC ubiquitin ligases–cell cycle regulators already well established in control of the chromosome replication cycle–also had fundamental roles in controlling the centrosome cycle (Freed et al., 1999; Hinchcliffe et al., 1999; Lacey et al., 1999; Meraldi et al., 1999; Vidwans et al., 1999). Since then, a number of other cell cycle regulators have been directly implicated in the centrosome cycle, many of which are described in the accompanying reviews. Here we will focus on the role of ubiquitin ligases in controlling the centrosome cycle, considering both those known or postulated core centrosomal factors that are directly ubiquitinated, as well as ubiquitination of specific cell cycle regulators–including kinases and ubiquitin ligases themselves–that more globally control the centrosome cycle. First, we will review the biochemistry of ubiquitin ligases, and then return to the role of these enzymes in the various phases of the centrosome cycle.

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  1. Programs in Chemical Biology and Cancer Biology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, 94305-5324, California, CA, USA

    David V Hansen, Jerry Y Hsu, Brett K Kaiser, Peter K Jackson & Adam G Eldridge

  2. Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, 94305-5324, California, CA, USA

    David V Hansen, Jerry Y Hsu, Brett K Kaiser, Peter K Jackson & Adam G Eldridge

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Appendix

Appendix

A primer on ubiquitylation enzymes

Ubiquitin-dependent proteolysis occurs following the covalent addition of a polyubiquitin chain to a specific target protein. Polyubiquitylation targets proteins to the 26S proteasome, an ATP- and ubiquitin-dependent protease complex. The cascade of E1, E2 and E3 enzymes activate the ubiquitin and facilitate the assembly of the multiubiquitin chain. Generally, the E3s are the most diverse group.

Ubiquitin (Ub)

A 76 amino acid protein with the C-terminal glycine (Gly76) residue capable of forming an isopeptide bond with a side chain lysine on a target protein or one of the side chain lysines of ubiquitin itself (notably lysine 48). There are a number of ubiquitin-like molecules (UBLs), such as SUMO-1 and NEDD8/Rub1, that are added as monomers to side-chain lysines.

E1, a ubiquitin-activating enzyme

Ubiquitin is activated by the E1 enzyme and ATP to form a thioester linkage between the C-terminal glycine 76 and a conserved active site cysteine. Uba1 is the major form of this enzyme in yeast and humans.

E2, a ubiquitin-conjugating enzyme

After activation by the E1, ubiquitin is transesterified to a conserved cysteine of an E2 enzyme. There are 13 E2s in yeast and approximately 30–50 in vertebrates. The genetic name for these enzymes includes the three letter code ‘Ubc’. Except for Ubc9 (a SUMO-conjugating enzyme) and Ubc12 (a NEDD8/Rub1 conjugating enzyme), the Ubcs have varying genetically defined functions in ubiquitylation, but some overlapping roles. Ubc3 is also known as Cdc34, a crucial E2 enzyme in the SCF ubiquitin ligase.

E3, a ubiquitin ligase

The E3 ubiquitin ligases couple with the E2s to bind to substrate and assemble a multiubiquitin chain on the substrate. For the HECT domain E3s, the E3 itself forms a thioester with ubiquitin and presumably participates in transferring the ubiquitin directly to the substrate. For the E3 complexes containing cullins or RING finger proteins, no direct thioester between E3 and ubiquitin has been identified. In these E3 classes, the ubiquitin ligase might function to facilitate the interaction between substrate and E2 enzyme (see main text for further discussion).

E4, a multiubiquitin chain assembly factor

The budding yeast UFD2 has been called an E4 protein. The protein binds to multiubiquitin chains and may facilitate part of the ubiquitin-dependent proteolysis pathway following ubiquitin chain assembly.

The 26S proteasome

The proteasome is an abundant protease complex comprising a 20S core particle (CP) flanked by two 19S regulatory particles (RP). The CP is cylindrical, with narrow channels feeding a central cavity with multiple protease sites. The regulatory particles regulate substrate access on both ends of the core. The RP itself contains a base, which contains ATPase subunits thought to unfold substrates for access to the core, and a lid, which contains subunits for binding multiubiquitin chains and ubiquitin-deconjugating enzymes (isopeptidases).

Ubiquitin hydrolases (isopeptidases)

A diverse group of enzymes that hydrolyse isopeptide bonds in a multiubiquitin chain. These enzymes might provide regulatory and proofreading functions for assembly of ubiquitin chains and also allow recycling of ubiquitin monomers.

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Hansen, D., Hsu, J., Kaiser, B. et al. Control of the centriole and centrosome cycles by ubiquitination enzymes. Oncogene 21, 6209–6221 (2002). https://doi.org/10.1038/sj.onc.1205824

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