Three-dimensional organization of chromatids by nuclear envelope-associated structures.
ABSTRACT In evolution, the nuclear envelope (NE) arose from the prokaryotic plasma membrane. NE-associated structures, such as nuclear pore complexes (NPCs), the nuclear lamina, and nuclear envelope junctions (NEJs), have evolved to organize, among other things, chromatids within the three-dimensional space of the nucleus. NEJs represent patches of distinct integral membrane proteins of the outer and inner NE membranes, which, by interacting through conserved domains in the perinuclear space, closely align the two NE membranes. In a nuts-and-bolts configuration, the NEJs are linked to repetitive heterochromatin segments of chromatids on their nuclear side and to cytoskeletal elements on their cytoplasmic side. Cytoskeleton-generated mechanical forces are thereby effectively buffered to allow movement of nuclei in the viscous cytoplasm without disrupting the NE. Moreover, these same mechanical forces could generate distortions within the nucleus to facilitate chromatid fluctuations required for DNA repair, replication, and transcription. NPCs are the only route for bidirectional macromolecular transport between the cytoplasm and the nucleus. They also interact with euchromatin segments of chromatids. Thus far, crystallographic analyses of some nucleoporin contact sites suggest considerable plasticity. This flexibility has likely coevolved to not only buffer the mechanical forces propagated from the NEJs to the network of the more than 500 nucleoporins that make up a single NPC, but also impart fluctuations to NPC conformations for transporting large cargoes.
- SourceAvailable from: Martin Schuster[Show abstract] [Hide abstract]
ABSTRACT: Exchange between the nucleus and the cytoplasm is controlled by nuclear pore complexes (NPCs). In animals, NPCs are anchored by the nuclear lamina, which ensures their even distribution and proper organization of chromosomes. Fungi do not possess a lamina and how they arrange their chromosomes and NPCs is unknown. Here, we show that motor-driven motility of NPCs organizes the fungal nucleus. In Ustilago maydis, Aspergillus nidulans, and Saccharomyces cerevisiae fluorescently labeled NPCs showed ATP-dependent movements at ~1.0 µm/s. In S. cerevisiae and U. maydis, NPC motility prevented NPCs from clustering. In budding yeast, NPC motility required F-actin, whereas in U. maydis, microtubules, kinesin-1, and dynein drove pore movements. In the latter, pore clustering resulted in chromatin organization defects and led to a significant reduction in both import and export of GFP reporter proteins. This suggests that fungi constantly rearrange their NPCs and corresponding chromosomes to ensure efficient nuclear transport and thereby overcome the need for a structural lamina.The Journal of Cell Biology 07/2012; 198(3):343-55. DOI:10.1083/jcb.201201087 · 9.69 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: One of the main reasons for cancer mortality is caused by the highly invasive behavior of cancer cells, which often due to aggressive metastasis. Metastasis is mediated by various growth factors and cytokines, operating through numerous signaling pathways. Remarkably, all these metastatic signaling pathways must enter the nucleus through a single gatekeeper, the nuclear pore complex (NPC). NPCs are the only gateway between the cytoplasm and the nucleus. NPCs are among the largest proteinaceous assemblies in the cell and are composed of multiple copies of around 30 different proteins called nucleoporins. Here, we review what is currently known about the NPC, and its role in the mechanisms of tumor progression. We will also explore potential strategies to target metastatic pathways by manipulating the karyopherins (importins/exportins) of nucleocytoplasmic traffic through NPCs.CANCER AND METASTASIS REVIEW 02/2011; 30(2):239-51. DOI:10.1007/s10555-011-9287-y · 6.45 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The nuclear pore complex encloses a central channel for nucleocytoplasmic transport, which is thought to consist of three nucleoporins, Nup54, Nup58, and Nup62. However, the structure and composition of the channel are elusive. We determined the crystal structures of the interacting domains between these nucleoporins and pieced together the molecular architecture of the mammalian transport channel. Located in the channel midplane is a flexible Nup54⋅Nup58 ring that can undergo large rearrangements yielding diameter changes from ∼20 to ∼40 nm. Nup62⋅Nup54 triple helices project alternately up and down from either side of the midplane ring and form nucleoplasmic and cytoplasmic entries. The channel consists of as many as 224 copies of the three nucleoporins, amounting to a molar mass of 12.3 MDa and contributing 256 phenylalanine-glycine repeat regions. We propose that the occupancy of these repeat regions with transport receptors modulates ring diameter and transport activity.Cell 10/2011; 147(3):590-602. DOI:10.1016/j.cell.2011.09.034 · 33.12 Impact Factor