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  • Review Article
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The nucleoskeleton as a genome-associated dynamic 'network of networks'

Nature Reviews Molecular Cell Biology volume 12, pages 695–708 (2011)Cite this article

Subjects

Key Points

  • The cytoskeleton is mechanically anchored to various adhesion complexes that span the nuclear envelope, including LINC (links the nucleoskeleton and cytoskeleton) complexes and lamina-associated polypeptide 1 (LAP1)–luminal domain like LAP1 (LULL1)–torsin complexes. Nuclear envelope adhesions are, in turn, mechanically coupled to the nucleoskeleton.

  • Nuclear pore complexes (NPCs) are fundamentally connected to the genome and gene expression via pore-linked filaments, which branch and extend at least 350 nm into the nucleoplasm, connect to the nucleolus and mediate myosin- and actin-dependent export.

  • A-type and B-type lamins form separate networks of intermediate filaments. A long-term challenge in the field is to resolve how nuclear intermediate filaments organize in relation to the nuclear envelope, chromatin, NPCs and other nucleoskeletal structures and organelles. Lamins A, B1 and B2 have distinct tissue-specific expression patterns and cell-type-specific roles, including signalling. B-type lamins are mysterious contributors to genome function.

  • Emery–Dreifuss muscular dystrophy maps to six genes, including LMNA (which encodes A-type lamins) and emerin (EMD), identifying a group of proteins that may be responsible for mechanotransduction in muscle nuclei.

  • A matrix formed by nuclear mitotic apparatus (NuMA) proteins may provide a three-dimensional scaffold for other nucleoskeletal structures and chromosomes. The nucleoskeleton includes crosslinking proteins, such as spectrins and protein 4.1, which have links to NuMA and proposed elastic roles in the nucleoskeleton. Other spectrin-repeat nucleoskeletal proteins include nesprins (nuclear envelope spectrin-repeat proteins), muscle-specific A-kinase anchor protein (mAKAP) and bullous pemphigoid antigen 1 (BPAG1). Titin binds lamins directly and is essential for mitotic chromosome condensation.

  • Actin is required for transcription, chromatin remodelling, nuclear envelope assembly, nuclear export and movement within the nucleus. Actin forms unconventional polymers in the nucleus, and is regulated by more than 30 actin-binding proteins. The mechanisms by which actin polymers form and function in the nucleus are largely unknown and might be evolutionarily ancient.

  • Ten molecular motors (six myosins and four kinesins) localize in the nucleus. Nuclear myosin Ic is required for transcription by all three DNA-dependent RNA polymerases, as well as for other roles.

  • Open questions include the nuclear functions of several unconventional myosins, including myosin Va, myosin Vb, myosin VI, myosin XVI and myosin XVIIIb. Kinesins in the nucleus have enigmatic functions, possibly including roles in genome organization and movement.

  • During mitosis, the nucleoskeleton dynamically reorganizes to form the spindle matrix and actively support chromosome condensation and segregation.

  • Most nucleoskeletal components and functions are currently invisible to genome-scale analysis owing to lack of appropriate annotation for bioinformatics analysis. Use of the term nucleoskeleton for this field of research would therefore help to progress the field.

Abstract

In the cytosol, actin polymers, intermediate filaments and microtubules can anchor to cell surface adhesions and interlink to form intricate networks. This cytoskeleton is anchored to the nucleus through LINC (links the nucleoskeleton and cytoskeleton) complexes that span the nuclear envelope and in turn anchor to networks of filaments in the nucleus. The metazoan nucleoskeleton includes nuclear pore-linked filaments, A-type and B-type lamin intermediate filaments, nuclear mitotic apparatus (NuMA) networks, spectrins, titin, 'unconventional' polymers of actin and at least ten different myosin and kinesin motors. These elements constitute a poorly understood 'network of networks' that dynamically reorganizes during mitosis and is responsible for genome organization and integrity.

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Figure 1: The nucleoskeleton and cytoskeleton form intricate networks that are linked by complexes at the nuclear envelope.
Figure 2: Nuclear envelope adhesion and nucleoskeletal proteins organize the genome and mediate mechanotransduction.
Figure 3: Nucleoskeletal proteins may affect elasticity and tension.
Figure 4: Regulation of nuclear actin dynamics by nuclear actin-binding proteins.
Figure 5: Nuclear myosin and kinesin motors regulate a range of activities in the nucleus.

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Acknowledgements

We thank J. M. Berk for comments. We apologize to authors whose works could not be cited owing to space limitations. We gratefully acknowledge support from the US National Institutes of Health (RO1 GM48646 to K.L.W.).

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  1. Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Dan N. Simon & Katherine L. Wilson

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Correspondence to Katherine L. Wilson.

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Glossary

Nucleoskeleton

A conceptual term that is analogous to cytoskeleton and refers to all of the protein-based structures in the interphase nucleus, many of which also function during mitosis as the spindle matrix.

Mechanotransduction

Changes in gene expression triggered when cells experience mechanical force.

Centrosome

An organelle that anchors the minus ends of microtubules and is typically located near the nucleus in the centre of the cell. Also known as the microtubule-organizing centre or, in yeast, the spindle pole body.

Heterochromatin

Chromatin that is either transcriptionally silent ('facultative' heterochromatin) or lacks genes ('constitutive' heterochromatin; for example, centromeric DNA). Heterochromatin is more compact than transcriptionally active chromatin (euchromatin) but less compact than mitotic chromosomes.

Nucleolus

A conserved organelle that assembles around ribosomal DNA genes and is the site of ribosomal RNA transcription and the assembly of ribosome subunits (the translation machinery).

Cajal bodies

Conserved organelles that are involved in the biogenesis of small nuclear ribonucleoprotein (snRNP) particles (the transcription machinery).

Quiescence

The state in which cells stop proliferating (exit the cell cycle) but continue to function (for example, neurons and most other cells).

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Simon, D., Wilson, K. The nucleoskeleton as a genome-associated dynamic 'network of networks'. Nat Rev Mol Cell Biol 12, 695–708 (2011). https://doi.org/10.1038/nrm3207

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