Nuclear pore proteins and the control of genome functions

Abstract

Nuclear pore complexes (NPCs) are composed of several copies of ∼30 different proteins called nucleoporins (Nups). NPCs penetrate the nuclear envelope (NE) and regulate the nucleocytoplasmic trafficking of macromolecules. Beyond this vital role, NPC components influence genome functions in a transport-independent manner. Nups play an evolutionarily conserved role in gene expression regulation that, in metazoans, extends into the nuclear interior. Additionally, in proliferative cells, Nups play a crucial role in genome integrity maintenance and mitotic progression. Here we discuss genome-related functions of Nups and their impact on essential DNA metabolism processes such as transcription, chromosome duplication, and segregation.

Keywords: DNA damage; mitosis; nuclear envelope; nuclear genome; nuclear pore complex; nucleoporin; transcription control.

Figure 1.

NPC structure and molecular composition. Representation and predicted molecular composition of the vertebrate NPC. For the corresponding orthologs in other model organisms, see Rothballer and Kutay (2012). The NPC core scaffold and its components are represented in dark blue and light blue, the transmembrane subunits are shown in green, the cytoplasmic structures are represented in magenta, and the basket is shown in orange. Peripheral Nups showing higher mobility by FRAP, and other approaches are depicted in black.

Figure 2.

How NPC components affect genome functions. Proposed roles for NPC components in eukaryotic cells regardless of the cell cycle activity (constitutive roles/cell cycle-independent) reported in cycling cells (interphase) and during mitosis (mitosis). (1) NPCs mediate nucleocytoplasmic transport in every eukaryotic nucleus. (2–4) Nups have been proposed to participate in transcriptional regulation, promoting either transcriptional activation (green circles) or repression (red circles) independently of the proliferative status of the cell. Gene expression regulation by Nups takes place mainly at the NE-embedded NPC in yeast (2,3), while in metazoans (4), a subset of mobile Nups (see also Fig. 1) can relocate to the nuclear interior to perform the same gene regulatory functions. (5) In both compartments, Nups might influence chromatin structure or organization of the tethered regions in collaboration with other factors (pink circles). (6) In proliferating cells, NPC–chromatin contacts must be regulated (arrow) during S phase to avoid replication fork collapse. (7) NPC components might facilitate the repair of a subset of persistent DNA lesions recruited to the NPC vicinity in yeast. (8) In organisms with open mitosis, NPC components assist NE breakdown and centrosome migration. (9) After NPC disassembles, some NPC components accumulate at the kinetochores, while other remain dispersed throughout the mitotic cell. By ensuring the localization and function of key mitotic components, Nups promote accurate spindle assembly, mitotic progression, and faithful chromosome segregation.