The Ran-GTPase and cell-cycle control

RCC1, the chromatin-bound guanine-nucleotide exchange factor (GEF) for the small nuclear GTPase, Ran, is required for coordinating the onset of mitosis with S-phase completion in mammalian cells. Other defects in the Ran-GTPase network also result in disruption of cell-cycle processes such as DNA replication, exit from mitosis and, at least in budding yeast, accurate chromosome segregation. However, the Ran system is now best known for its pivotal role in nucleocytoplasmic transport, where RanGTP is used as a positional flag for the nucleus during interphase. Ran's effectors are the shuttling transport factors, importins and exportins, which facilitate the transit of cargoes between the nucleus and cytoplasm: RanGTP regulates their cargo-binding properties so that they can move their cargo in the correct direction. RanGTP also plays a separate role during mitosis, influencing microtubule polymerisation, possibly specifically in the vicinity of chromosomes. Most recently, Ran has been shown to be crucial for the regeneration of a nuclear envelope after exit from mitosis. So, can the problems with cell-cycle progression and control induced by perturbing the Ran-system be attributed to defects in these three processes? This article examines this issue, concentrating on vertebrate systems. BioEssays 23:77-85, 2001.