The genetic material of eukaryotic cells is enclosed by the nuclear envelope, a double membrane consisting of an outer nuclear membrane (ONM) and an inner nuclear membrane (INM). The INM is associated with a protein mesh called the nuclear lamina, which provides structural support to the nuclear envelope and is known to be involved in the regulation of chromatin organization and gene expression (reviewed in [1]). The nuclear envelope is perforated by nuclear pore complexes (NPCs) that allow and regulate the bidirectional transport of macromolecules between the nucleus and cytoplasm. Additionally, NPCs participate in a wide range of other nuclear processes, including chromatin organization, gene regulation and DNA repair, which will be the focus of this review.

NPCs are large protein assemblies embedded in the nuclear envelope. They comprise a symmetric scaffold composed of an inner ring anchored in the nuclear envelope and two outer rings called the cytoplasmic and nuclear rings [2], [3]. The inner ring anchors the components of the central channel whereas the outer rings anchor the cytoplasmic filaments and the nuclear pore basket, providing asymmetry to the NPC [4]. The diverse functions of the NPCs are largely attributed to the unique properties of their protein subunits, the nucleoporins (Nups). Approximately one-third of the Nups contain phenylalanine-glycine (FG) repeat sequences (e.g. FG, GLFG, and FxFG) (reviewed in [5], [6]). FG-Nups have the ability to undergo phase separation in vitro [7], [8], a process in which molecules or proteins self-associate to form liquid or gel-like droplets, also known as condensates (reviewed in [9], [10]).

The formation of condensates underlies several cellular processes, such as chromatin compaction [11] and DNA repair [12]. In the case of FG-Nups, phase separation is thought to be involved in the regulation of nucleocytoplasmic transport. Indeed, FG-Nups are mainly located in the central channel, where their phase separation properties contribute to the selective bidirectional transport of molecules across the nuclear pore [13], [14], [15], [16], [17], [18], [19], [20]. While small cargoes, such as metabolites, ions and small proteins, can readily diffuse through the permeability barrier, the transport of larger cargoes is mediated by nuclear transport receptors (NTRs), which recognize a nuclear localization signal (NLS) or nuclear export signal (NES). FG-Nups interact with NTRs, through rapid binding and unbinding, which allow fast and selective transport [5].

This review will delve into the various roles of NPCs and nucleoporins in 3D chromatin architecture, gene regulation and genome stability. While work performed in yeast has tremendously advanced our knowledge in this field (for extensive reviews on yeast studies, see [21], [22], [23]), this review will focus on recent studies performed in metazoans. When relevant, impact of these non-conventional NPC functions in developmental, physiological or pathological processes will be highlighted.