PubMed Health⌕ Search
Home/Archive/PubMed

PubMed · 16896351

The anaphase promoting complex/cyclosome: a machine designed to destroy.

Jan-Michael Peters
View original source ↗Export metadata ↓

Abstract

The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. Recent discoveries have revealed an unexpected multitude of mechanisms that control APC/C activity, and have provided a first insight into how this unusual ubiquitin ligase recognizes its substrates.

Explore related subjects

Anaphase-Promoting Complex-CyclosomeAnimalsCatalytic DomainHumansMultienzyme ComplexesProtein Processing, Post-TranslationalSubstrate SpecificityUbiquitinUbiquitin-Protein Ligase ComplexesJournal ArticleResearch Support, Non-U.S. Gov'tReview

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Jan-Michael Peters. 2006-08-09. The anaphase promoting complex/cyclosome: a machine designed to destroy.. https://doi.org/10.1038/nrm1988

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2026

Viral inhibition of the anaphase promoting complex enhances replication by elevating nucleotide pools.

The anaphase promoting complex/cyclosome (APC/C) is a large, ubiquitin ligase and a central regulator of cell cycle progression. By targeting key substrates for degradation during mitosis and G1 phase, the APC/C coordinates metabolic fluctuations that occur during the cell cycle. A diverse range of viruses have convergently evolved mechanisms to bind and inhibit the APC/C; however, a molecular understanding for these interactions has never been demonstrated. Here, we use chicken anemia virus (CAV), a small single-stranded DNA virus encoding only three proteins, to demonstrate the importance of viral APC/C inhibition during replication. We show that the Vp3 protein of CAV inhibits the APC/C, causing a dramatic mitotic arrest during infection. The mutant virus lacking Vp3 is defective for replication and can be rescued by APC/C inhibition. Metabolomic profiling during CAV infection revealed that Vp3 expression mediates a broad increase in nucleotide pools. Moreover, viral inhibition of the APC/C resulted in stabilization of enzymes required for nucleotide biosynthesis. These findings suggest that the APC/C is a general target of many viruses to elevate nucleotide levels and facilitate viral genome replication.

Anaphase-Promoting Complex-Cyclosome↗
PubMed2007

Hiding human thymidine kinase 1 from APC/C-mediated destruction by thymidine binding.

Thymidine kinase 1 (TK1) is a key cytosolic enzyme in the salvage pathway for dTTP synthesis. In mitotic exit, human TK1 (hTK1) is degraded via the anaphase-promoting complex/cyclosome (APC/C)-Cdh1 pathway to limit dTTP production. In this study, we show that thymidine binding stabilizes hTK1 during growth arrest. By in vitro degradation, ubiquitination, and Cdh1 binding analyses, we provide direct evidence that thymidine binding protects wild-type hTK1 protein from APC/C-Cdh1-mediated destruction. In contrast, mutant-type hTK1 protein defective in thymidine binding ability could still be polyubiquitinated by APC/C-Cdh1 in the presence of thymidine. These results suggest that the status of thymidine binding to hTK1 protein determines its susceptibility to degradation due to APC/C targeting. Our in vivo experimental data also demonstrated that thymidine treatment abolished Cdh1/proteasome-responsive suppression of hTK1 expression. Moreover, exposure of mitotic-arrested K562 cells to thymidine (100 microM) stabilized endogenous TK1, causing nucleotide imbalance in the early G1 phase and an increase of S phase accumulation. In conclusion, thymidine is not only a substrate of TK1 but also acts as its expression regulator by modulating its proteolytic control during mitotic exit, conferring a feed-forward regulation of dTTP formation.

Anaphase-Promoting Complex-Cyclosome↗
PubMed2007

Aberrant monomethylation of histone H4 lysine 20 activates the DNA damage checkpoint in Drosophila melanogaster.

PR-Set7 is a histone methyltransferase that specifically monomethylates histone H4 lysine 20 (K20) and is essential for cell proliferation. Our results show that in PR-Set7 mutants, the DNA damage checkpoint is activated. This phenotype is manifested by reduction in both the mitotic and the S phase indexes, a delay in the progression through early mitosis, and strong reduction of cyclin B. Furthermore, in a double mutant of PR-Set7 and mei-41 (the fly ATR orthologue), the abnormalities of mitotic progression and the cyclin B protein level were rescued. PR-Set7 also showed a defect in chromosome condensation that was enhanced in the double mutant. We therefore propose that monomethylated H4K20 is involved in the maintenance of proper higher order structure of DNA and is consequently essential for chromosome condensation.

Anaphase-Promoting Complex-Cyclosome↗