Nuclear pore complexes: guardians of the nuclear genome

Abstract

Eukaryotic cell function depends on the physical separation of nucleoplasmic and cytoplasmic components by the nuclear envelope (NE). Molecular communication between the two compartments involves active, signal-mediated trafficking, a function that is exclusively performed by nuclear pore complexes (NPCs). The individual NPC components and the mechanisms that are involved in nuclear trafficking are well documented and have become textbook knowledge. However, in addition to their roles as nuclear gatekeepers, NPC components-nucleoporins-have been shown to have critical roles in chromatin organization and gene regulation. These findings have sparked new enthusiasm to study the roles of this multiprotein complex in nuclear organization and explore novel functions that in some cases appear to go beyond a role in transport. Here, we discuss our present view of NPC biogenesis, which is tightly linked to proper cell cycle progression and cell differentiation. In addition, we summarize new data suggesting that NPCs represent dynamic hubs for the integration of gene regulation and nuclear transport processes.

Figure 1. Composition of the NPC

Schematic of the yeast (left) and mammalian (right) NPCs. The framed boxes represent individual Nups or subcomplexes. The transmembrane Nups are depicted in orange, the soluble scaffold components in red, the central core Nups in grey, the components of the cytoplasmic filaments in purple and the members of the nuclear basket in blue. Note that the relative position of the components is not meant to represent the structure of the NPC beyond this general organization.

Figure 2. Model for mammalian NPC assembly mechanisms in mitosis and interphase

The sequences of events leading to post-mitotic (left) or interphase (right) NPC assembly are represented from top to bottom. The chromatin is depicted in grey, the intensity of the color reflecting its compaction state.

Figure 3. A schematic representation of three alternative hypotheses for the functional roles of the genome-NPC contacts

As demonstrated in yeast, the NE-embedded NPCs may bind active genes at opposing ends, forming gene loops, to establish assembled transcription and processing domains that are “remembered” through cell divisions. Alternatively, and as may be more prevalent in metazoa, the NE-associated NPCs may interact with boundary or non-transcribing genomic regions to similarly set up gene expression domains or general nuclear chromatin organization. An intriguing possibility would be the use of such contacts for “remembering” a particular chromatin organization in differentiating or differentiated cells, the latter of which do not turn over their NPCs and remain stable over long periods of time. Finally, NE-independent NPC components may bind active genes in the nucleoplasm for the similar purposes of setting up local transcription and processing organization, which may involve gene looping or even gene contacts between distant loci.