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Orchestrating nuclear envelope disassembly and reassembly during mitosis

Nature Reviews Molecular Cell Biology volume 10, pages 178–191 (2009)Cite this article

Key Points

  • The nucleus is surrounded by the nuclear envelope (NE), which is formed by two juxtaposed membranes, termed the inner and outer nuclear membranes. A protein meshwork of intermediate filament proteins — the nuclear lamina — is attached to the inner face of the NE. The NE is perforated by holes that are occupied by nuclear pore complexes (NPCs), which serve the selective transport of macromolecules between nucleus and cytoplasm.

  • The NE is a highly dynamic structure that is completely disassembled and reassembled during open mitosis in higher eukaryotes. These mitotic changes are subject to both spatial and temporal control mechanisms that are embedded in the more general network that controls cell division.

  • NE breakdown (NEBD) involves the disassembly of NPCs, the disintegration of the nuclear lamina and the retraction of NE membranes into the membrane system of the endoplasmic reticulum. NEBD is triggered by the concerted action of mitotic kinases, some of which are known to directly contribute to NEBD.

  • Some of the protein constituents of NPCs, termed nucleoporins, have prominent roles during specific steps of mitotic progression, such as spindle assembly and sister chromatid separation.

  • NE reformation occurs around a compacted mass of segregated chromatin in each daughter cell. NPC assembly is initiated in anaphase by the deposition of prepores on chromatin. Nuclear membrane reformation commences with the attraction of ER tubules to the surface of chromatin, which then flatten to form membrane sheets. DNA-binding inner nuclear membrane proteins have a pivotal role in establishing chromatin–membrane contacts. Subsequent events in nuclear reformation include the formation of a closed NE that contains fully assembled, transport-competent NPCs, and the reformation of the nuclear lamina.

Abstract

Cell division in eukaryotes requires extensive architectural changes of the nuclear envelope (NE) to ensure that segregated DNA is finally enclosed in a single cell nucleus in each daughter cell. Higher eukaryotic cells have evolved 'open' mitosis, the most extreme mechanism to solve the problem of nuclear division, in which the NE is initially completely disassembled and then reassembled in coordination with DNA segregation. Recent progress in the field has now started to uncover mechanistic and molecular details that underlie the changes in NE reorganization during open mitosis. These studies reveal a tight interplay between NE components and the mitotic machinery.

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Figure 1: The main structural features of the nuclear envelope.
Figure 2: From 'open' to 'closed' mitosis.
Figure 3: Nuclear envelope breakdown during 'open' mitosis.
Figure 4: Nucleoporins in spindle assembly and kinetochore function.
Figure 5: Nuclear envelope reassembly after mitosis.

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Acknowledgements

We apologize to all colleagues whose papers could not be covered owing to space limitations. We thank W. Antonin, P. Meraldi and I. Zemp for critical reading of the manuscript, Y. Barral, H. Meyer, I. Sumara and D. Gerlich for discussions and Y. Turgay for help with image acquisition. Our work is supported by the Swiss National Science Foundation.

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  1. Institute of Biochemistry, Eidgenössische Technische Hochschule Zurich, HPM F11.1, Schafmattstrasse 18, Zurich, 8093, Switzerland

    Stephan Güttinger, Eva Laurell & Ulrike Kutay

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  1. Stephan Güttinger
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Correspondence to Ulrike Kutay.

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Supplementary information S1 (table) | Mitotic phosphorylation sites in nucleoporins and NE-associated proteins* (PDF 271 kb)

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Glossary

Nuclear pore complex

(NPC). A multisubunit protein complex in the nuclear envelope that serves as a transport channel between the nucleus and the cytoplasm. NPCs are permeable for small molecules but restrict the passive diffusion of macromolecules larger than 30 kDa.

Nuclear lamina

A fibrous intermediate filament network that consists of lamins and underlies the inner nuclear membrane.

Kinetochore

A multimeric protein complex that is formed on centromeric DNA and mediates the attachment of spindle microtubules to chromosomes during mitosis.

Guanine nucleotide-exchange factor

A protein that catalyses the exchange of GDP for GTP on G proteins.

GTPase-activating protein

A factor that stimulates the intrinsic GTPase activity of small GTPases, thereby inducing the hydrolysis of bound GTP to GDP.

Nucleoporin

A protein constituent of the nuclear pore complex (NPC). Each NPC is composed of ∼30 different nucleoporins, which are present in multiples of 8, reflecting the eight-fold rotational symmetry of the NPC. Approximately one-third of nucleoporins contain Phe-Gly repeats that are binding sites for transport receptors.

Centrosome

The microtubule-organizing centre in animal cells. It consists of a pair of centrioles surrounded by the pericentriolar matrix. During mitosis, centrosomes serve as spindle poles.

Cyclin-dependent kinase

(CDK). A family of protein kinases, the activity of which depends on the formation of a complex with cyclin subunits. Different CDK–cyclin complexes orchestrate distinct steps in the cell cycle.

Nocodazole

A drug that inhibits the polymerization of microtubules. Nocodazole-treated cells enter mitosis but cannot form a mitotic spindle and consequently arrest in prometaphase.

Topoisomerase

An enzyme that binds to DNA and catalyses its unknotting by transiently breaking phosphodiester bonds.

Condensin

A five-subunit protein complex that is associated with mitotic chromosomes and is implicated in chromosome condensation. Two types of condensin complexes exist in vertebrate cells — condensin I and II — which share the ATPase subunits structural maintenance of chromosomes 2 (SMC2) and SMC4.

Reticulon

A member of the reticulon family of membrane proteins that are associated with the tubular endoplasmic reticulum (ER). Reticulons as well as members of the DP1/YOP1 protein family contain two long hydrophobic domains that are each proposed to insert as wedge-like hairpins into lipid bilayers and to promote the formation of ER tubules.

COPI

(Coatomer protein complex I). A cytosolic protein complex that is composed of seven polypeptides that coats membrane transport vesicles. The COPI complex is required for the formation of Golgi-derived vesicles for retrograde transport to the ER.

NUP107–160 complex

An essential, multimeric nucleoporin subcomplex that consists of ∼10 subunits. It is the major constituent of the central nuclear pore complex (NPC) scaffold and it symmetrically localizes to both sides of the NPC.

Centromere

A specialized heterochromatin region on each chromosome where sister chromatids are held together and on which the kinetochore is formed during mitosis.

RanBP2

(Ran-binding protein 2). The major constituent of the cytoplasmic filaments of the nuclear pore complex. RanBP2 has small ubiquitin-like modifier (SUMO) E3 ligase activity and forms a stable complex with sumoylated Ran GTPase-activating protein 1 (RanGAP1) throughout the cell cycle. Furthermore, it contains four Ran-binding domains, which facilitate the disassembly of RanGTP-containing export complexes.

SUMO

(Small ubiquitin-like modifier). A ubiquitin-like polypeptide that can be covalently attached to Lys residues on target proteins by an enzyme cascade. Unlike ubiquitin, it does not target proteins for proteasomal degradation. Attachment of SUMO to Ran GTPase-activating protein 1 (RanGAP1) is required for the localization of RanGAP to nuclear pore complexes in metazoan cells.

CRM1

A RanGTP-binding nuclear transport receptor that mediates the export of proteins that have Leu-rich nuclear export signals.

Cold-stable microtubules

Microtubules that resist depolymerization at low temperatures.

Haploinsufficient

A gene is haploinsufficient in a diploid organism when one functional allele is insufficient to maintain a wild-type state.

Securin

An inhibitor of the enzyme separase that cleaves the sister chromatin cohesion protein 1 (SCC1) subunit of cohesin to allow for sister chromatid separation.

Aneuploidy

Having too many or too few copies of a chromosome.

Sister chromatid

Two linked copies of a replicated chromosome that are the product of DNA replication. They are separated during the metaphase–anaphase transition of mitosis and then segregated into the two daughter cells.

Decatenation

The process in which rings or chains are untangled from each other. DNA sister chromatids become entangled or catenated as a consequence of DNA replication and must be decatenated to allow for sister chromatid separation and segregation during mitosis.

Anaphase bridge

Chromatin fibres that connect the two separating chromosome masses during anaphase. Anaphase bridges can lead to chromosome amplifications, translocations or deletions and are considered a hallmark of genomic instability.

Chromokinesin

A subgroup of molecular motors belonging to the kinesin family that associate with chromosome arms during mitosis.

Micronucleus

A nuclear envelope-enclosed chromosome (or group of chromosomes) that is not incorporated with most of the chromosomes into the newly formed nucleus during cell division.

AAA+ ATPase

(ATPase associated with various cellular activities). A protein that contains one or two ATP-binding domains, and that forms ring-like oligomers and functions in conformational remodelling of macromolecules.

Aurora B

A member of the Aurora family of Ser/Thr protein kinases. Aurora B is a component of the chromosome passenger complex and is required for several aspects of mitosis, such as kinetochore function, the spindle assembly checkpoint and cytokinesis.

E3 ubiquitin ligase

The last enzyme in a cascade of enzymes (E1, E2 and E3) that mediates the attachment of mono- or polyubiquitin to target proteins. E3 enzymes are binding platforms for E2 ligases and substrate proteins and thereby confer specificity to the ubiquitylation reaction.

Annulate lamellae

Stacks of membrane cisternae, usually localized in the cytoplasm, that are densely packed with nuclear pore complexes.

SNARE

(Soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor). A large protein family of membrane-anchored coiled-coil proteins that contribute to the specificity of membrane trafficking and promote membrane fusion.

ERC

(Extrachromosomal ribosomal DNA circle). A self-replicating, non-centromeric plasmid that is generated sporadically by homologous recombination in chromosomal repeats of ribosomal DNA.

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Güttinger, S., Laurell, E. & Kutay, U. Orchestrating nuclear envelope disassembly and reassembly during mitosis. Nat Rev Mol Cell Biol 10, 178–191 (2009). https://doi.org/10.1038/nrm2641

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