Abstract
The GTPase Ran has a key role in nuclear import and export, mitotic spindle assembly and nuclear envelope formation. The cycling of Ran between its GTP- and GDP-bound forms is catalyzed by the chromatin-bound guanine nucleotide exchange factor RCC1 and the cytoplasmic Ran GTPase-activating protein RanGAP. The result is an intracellular concentration gradient of RanGTP that equips eukaryotic cells with a ;genome-positioning system' (GPS). The binding of RanGTP to nuclear transport receptors (NTRs) of the importin beta superfamily mediates the effects of the gradient and generates further downstream gradients, which have been elucidated by fluorescence resonance energy transfer (FRET) imaging and computational modeling. The Ran-dependent GPS spatially directs many functions required for genome segregation by the mitotic spindle during mitosis. Through exportin 1, RanGTP recruits essential centrosome and kinetochore components, whereas the RanGTP-induced release of spindle assembly factors (SAFs) from importins activates SAFs to nucleate, bind and organize nascent spindle microtubules. Although a considerable fraction of cytoplasmic SAFs is active and RanGTP induces only partial further activation near chromatin, bipolar spindle assembly is robustly induced by cooperativity and positive-feedback mechanisms within the network of Ran-activated SAFs. The RanGTP gradient is conserved, although its roles vary among different cell types and species, and much remains to be learned regarding its functions.
Highlights
The Ras-related GTPase Ran controls many aspects of genome compartmentalization in the nucleus in eukaryotes, including the regulation of nucleo-cytoplasmic transport and formation of the nuclear envelope, as well as genome segregation to daughter cells by the mitotic spindle (Clarke and Zhang, 2004; Goodman and Zheng, 2006; Pemberton and Paschal, 2005; Terry et al, 2007)
This Commentary focuses on how the RanGTP gradient is generated in mitotic cells and how it functions in spindle assembly by spatially directing the activity and/or localization of spindle assembly factors (SAFs) and mitotic regulators (Table 1)
All five human homologues of the X. laevis HURP complex (Eg5, hTOG/XMAP215, TPX2, HURP, Aurora A) (Koffa et al, 2006; Sillje et al, 2006) are expressed coordinately with each other and with mitotic markers in cells derived from 22 different human tumors (Tsou et al, 2003; Wong and Fang, 2006), showing that, in some cancer cells, key Ran-regulated SAFs are upregulated at the same time
Summary
The Ras-related GTPase Ran controls many aspects of genome compartmentalization in the nucleus in eukaryotes, including the regulation of nucleo-cytoplasmic transport and formation of the nuclear envelope, as well as genome segregation to daughter cells by the mitotic spindle (Clarke and Zhang, 2004; Goodman and Zheng, 2006; Pemberton and Paschal, 2005; Terry et al, 2007). The cycling of Ran between its GTP- and GDP-bound forms is controlled by a pair of exquisitely Ran-specific regulators with distinct localizations: Ran’s guanine nucleotide exchange factor (GEF) regulator of chromatin condensation 1 (RCC1) is imported to the nucleus and binds to chromatin, whereas its GTPaseactivating protein RanGAP is cytoplasmic. RanGTP-gradient-regulated NTR-cargo-complex assembly and disassembly reactions continue after nuclear envelope breakdown in Metazoa and perform essential mitotic roles. This Commentary focuses on how the RanGTP gradient is generated in mitotic cells and how it functions in spindle assembly by spatially directing the activity and/or localization of spindle assembly factors (SAFs) and mitotic regulators (Table 1). Binding of RCC1 to chromatin drives RanGTP-gradient formation RCC1 binds directly to dsDNA through its unusually processed Nterminal tail (in which the N-terminal serine or proline residue is methylated) (Chen et al, 2007) and to histones H2A or H2B on the nucleosome (Nemergut et al, 2001) by an adjacent domain
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