Nuclear pore complexes and regulation of gene expression

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Highlights

  • Nuclear pore complexes and nucleoporins have many transport-independent functions.

  • Nuclear pore complexes play key roles in gene expression regulation.

  • In yeast, the activity of many inducible genes is regulated at nuclear pore complexes.

  • In metazoans, many nucleoporins regulate gene expression inside the nucleus and away from nuclear pore complexes.

Nuclear pore complexes (NPCs), are large multiprotein channels that penetrate the nuclear envelope connecting the nucleus to the cytoplasm. Accumulating evidence shows that besides their main role in regulating the exchange of molecules between these two compartments, NPCs and their components also play important transport-independent roles, including gene expression regulation, chromatin organization, DNA repair, RNA processing and quality control, and cell cycle control. Here, we will describe the recent findings about the role of these structures in the regulation of gene expression.

Introduction

In 1950, Callan and Tomlin used Xenopus laevis oocytes to perform the first electron microcopy studies of the nuclear envelope (NE) and observed that it was perforated by many large pores [1]. This was the first description of nuclear pore complexes (NPCs). Our understanding of NPCs has come a long way since that initial observation. Thanks to a momentous amount of work performed by many different groups over the last six decades we now know that NPCs are giant multiprotein channels of about 110 MDa in mammals that represent the sole gateway into the nucleus. At the structural level, NPCs have an eightfold rotational symmetry, and consist of a core ring embedded in the NE, two outer rings, one cytoplasmic and one nuclear, and eight filaments attached to these rings [2]. The nuclear filaments are also joined in a distal ring assembling a structure known as the nuclear basket. Despite being one of the largest protein complexes of eukaryotic cells these structures have a rather simple composition and are built by the repetition of roughly 30 different proteins known as nucleoporins [3, 4]. Recent studies combining structural information from the NPC itself and from individual nucleoporins has resulted in an unprecedented resolution of this structure [5•, 6•, 7].

In addition to their main function as mediators of nucleocytoplasmic molecule exchange, increasing evidence shows that NPCs regulate multiple cellular processes in a transport-independent manner [2]. Probably the most studied so far, and the focus of this review, is their role in genome organization and gene expression regulation.

Section snippets

Gene expression regulation by NPCs in yeast

The first evidence for a role of nuclear pore complexes in the regulation of gene expression came from studies in Saccharomyces cerevisiae. Though the initial observations of NPCs association with repressed telomeric and subtelomeric chromatin fueled the idea that the nuclear periphery was always associated with gene silencing, [8, 9], Menon et al. were the first ones to show that the Nup84 scaffold subcomplex of the NPC could act as transcriptional activator by itself [10]. Two other later

Gene expression regulation by NPCs in metazoans

Our knowledge of NPC-mediated regulation of gene expression in metazoans is considerably more limited than in yeast. The first connection of NPC components with chromatin modulation/gene expression regulation was described in Drosophila melanogaster with the identification of two nucleoporins, mTor/TPR and Nup153, as partners of the MSL dosage compensation complex [46]. This work showed that both nucleoporins were required for the localization of the MSL complex to the X chromosome and for the

Conclusions

Since the discovery of the first nucleoporin–gene interactions just 10 years ago, it has become clear that the NPC and its components play a pivotal role in the regulation of gene expression in multiple organisms. In this review, we have mostly focused in the positive regulation of gene expression by these proteins, but NPCs and nucleoporins have also been shown to associate and regulate silent/inactive chromatin [8, 26, 57••, 61, 62, 63, 64, 65]. Understanding how NPCs contribute to modulating

Acknowledgements

We apologize to all colleagues whose work could not be cited directly owing to space limitation. M.A.D. is a Pew Scholar in the Biomedical Sciences. Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number R01AR065083. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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