Ran-bound RCC1 (bottom) is less mobile (circle, left to right) at chromosomes than is unbound RCC1 (top).

Gradients of the small GTPase Ran are important throughout the cell cycle. High nuclear RanGTP concentrations in interphase cells regulate nuclear transport. During mitosis, chromosome-localized RanGTP releases spindle assembly factors from sequestration by importins. On page 635, Li et al. demonstrate that RanGTP accumulates at chromosomes because the complex of Ran and its guanine nucleotide exchange factor (GEF) binds strongly to chromatin.

GTP-bound Ran is produced by the GEF RCC1, which binds only weakly to histones. Using a GFP-tagged version, the authors show that RCC1 is highly mobile and exchanges rapidly between free and chromatin-bound states. As RCC1 has strong GEF activity in the presence or absence of chromatin, the authors were interested in determining how RanGTP production is limited to chromosomes. They found that Ran-bound RCC1 had a stronger chromosome association. Locking RCC1 to Ran, using a mutant version of Ran, immobilized RCC1 on chromosomes. Ran also enhanced RCC1 binding to chromatin in vitro. Only nucleotide exchange, which displaces RCC1 from Ran, released the GEF and RanGTP from chromosomes.

The increased affinity of the complex for chromosomes can be explained by its binding geometry. RCC1 binds histones H2A and H2B, whereas Ran binds weakly to histones H3 and H4. The complex is therefore well suited to bind to nucleosome octamers. Thus, exploiting the geometry of nucleosomes is a simple way to couple GTP exchange to chromatin-bound Ran. ▪