RESEARCH HIGHLIGHTS

CELL CYCLE The transition from mitosis (M phase) substrates were consistently degraded to G1 phase is controlled by complex throughout G1 phase, -A degra- interactions between two key compo- dation gradually became blocked as nents of the cell-cycle machinery, the cells progressed through G1. The What goes anaphase-promoting complex/cyclo- degradation of cyclin A relied specifi- some (APC/C) and cyclin A. The cally on the presence of a threshold around… APC/C is a multisubunit lig- level of the ubiquitin-conjugating ase that controls sister-chromatid sepa- enzyme (E2) UBCH10, whereas other ration and triggers mitotic exit APC/C substrates were still degraded a A B through the ubiquitin-mediated in the presence of another E2, f degradation of proteins (including, in UBCH5. In keeping with this, the A B A B M phase, cyclin A). Cyclin A is an acti- authors showed that the level of A B APC/CCDC20 vator of the cell-cycle regulators CDK1 UBCH10 (but not UBCH5) fluctu- G2 and CDK2 and, in late G1 phase, is also ated during the , remaining UBCH10 e S M responsible for APC/C inactivation. high during cyclin-A degradation and Ub Ub How cyclin A can re-accumulate in staying low when cyclin A was stable. CDH1 A B APC/C the presence of active APC/C during Intriguingly, it was then found that b G1 Ub G1, and then inactivate the APC/C to UBCH10 was autoubiquitylated d APC/CCDH1 allow the re-accumulation of other before also being degraded by Ub A A APC/CCDH1 c UBCH10 mitotic during the DNA syn- APC/CCDH1 towards the end of G1. Ub CDH1 Ub thesis (S) and G2 phases, has been a However, this process was hampered APC/C A Ub puzzle. In Nature,Michael Rape and both by the slow rate of UBCH10 B UBCH10 Ub Ub B Marc Kirschner now report that they autoubiquitylation and by the pres- have solved the mystery, by studying ence of other APC/C substrates. In the effects that different components fact, the authors showed that, as long A Cyclin-A–CDK and regulators of the APC/C have on as other APC/C substrates are present the degradation of cyclin A. in G1, UBCH10 preferentially ubiq- B Cyclin-B–CDK APC/CCDH1 substrates Initially, using extracts from syn- uitylates them, rather than itself, Ub Ubiquitin chronized HeLa cells, the authors which effectively allows UBCH10 to showed that, whereas other APC/C orchestrate the timing of cyclin-A

NUCLEAR TRANSPORT dimensional density map. In this map, the seems to show cytoplasmic filaments in a basic structural features of NPCs could be cargo-bound state. By contrast, in NPCs of discerned: that is, eight cytoplasmic the ‘lumenal-ring’ class, the CP/T is in the filaments that are attached to the plane of the lumenal spoke ring, and only the cytoplasmic ring; the central, lumenal spoke base of the cytoplasmic filaments can be seen. Details of the ring; the central plug/transporter (CP/T) in This structure therefore seems to show the central channel; and the so-called cytoplasmic filaments that have disengaged doorway nuclear basket (the nuclear ring and the cargo and are free to move. Further distal ring that are connected by nuclear differences in the organization of the lumenal filaments). spokes and the appearance of the nuclear The nuclear pore complex (NPC) functions However, the authors also noted several basket could also be discerned between the as a doorway for the exchange of novel features — for example, the nuclear and NPC classes. macromolecules between the nucleus and the cytoplasmic filaments appeared more bent So, this work has shown that the CP/T is cytoplasm, and a detailed view of this and delicate than was previously reported, essentially cargo in transit and that NPCs doorway is now revealed by Baumeister, and the complex was less elongated along the undergo significant structural Medalia and colleagues in Science. nucleocytoplasmic axis. Furthermore, they rearrangements during cargo transit. In The size of NPCs makes their structural found that the size, shape and position of the addition, although many questions remain, it characterization difficult, and previous CP/T in the NPCs varied. The composition has shown that “…the application of cryo-ET structural studies have used isolated or and role of the CP/T have remained unclear, to transport-competent, intact nuclei holds detergent-extracted NPCs, which are but this observation indicates that it is great potential for a structural dissection of susceptible to the loss of certain components composed, at least in part, of cargo complexes the key steps involved.” and cargo. So, to get a more true-to-life view, that are arrested in transit. Rachel Smallridge Baumeister, Medalia and co-workers applied After further analysis, Baumeister, Medalia References and links cryo-electron tomography (cryo-ET) to and colleagues noted that the NPCs were in ORIGINAL RESEARCH PAPER Beck, M. et al. Nuclear whole, transport-active Dictyostelium one of two preferred states. In NPCs of the pore complex structure and dynamics revealed by cryoelectron tomography. Science 306, 1387–1390 (2004) discoideum nuclei. ‘cytoplasmic-filament’ class, the CP/T is in FURTHER READING Fahrenkrog, B. & Aebi, U. The nuclear From the resulting tomograms, they the plane of the cytoplasmic ring. The pore complex: nucleocytoplasmic transport and beyond. extracted 267 volumes that contained an cytoplasmic filaments are in a defined Nature Rev. Mol. Cell Biol. 4, 757–766 (2003) WEB SITE NPC and used averaging procedures to orientation and are connected to the CP/T by Wolfgang Baumeister’s laboratory: obtain an 8–9-nm-resolution, three- an elongated density. This structure therefore http://www.biochem.mpg.de/baumeister/

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