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Nuclear speckles: a model for nuclear organelles

Key Points

  • Speckles are dynamic subnuclear structures that contain pre-messenger RNA splicing factors and other proteins that are involved in transcription, 3′- end RNA-processing and reversible protein phosphorylation. The formation of speckles is regulated during the cell-division cycle.

  • Splicing factors cycle continually between speckles and the nucleoplasm. Their size and shape results from the dynamic exchange of factors into and out of speckles.

  • A reversible protein phosphorylation mechanism can regulate the movement of speckle components between speckles and other nuclear structures. It is likely that protein–protein interactions are primarily responsible for the formation and integrity of speckles.

  • Speckles contain little or no DNA and are not principal sites of transcription. Instead, they function as assembly/modification sites that can supply active splicing factors to sites of transcription.

  • We propose a 'regulated-exchange' model to account for the steady-state level of proteins in speckles. This envisages that the concentration of factors that are localized in speckles results from a regulated and cell-type-specific basal exchange rate of speckle components.

Abstract

Speckles are subnuclear structures that are enriched in pre-messenger RNA splicing factors and are located in the interchromatin regions of the nucleoplasm of mammalian cells. At the fluorescence-microscope level they appear as irregular, punctate structures, which vary in size and shape, and when examined by electron microscopy they are seen as clusters of interchromatin granules. Speckles are dynamic structures, and both their protein and RNA–protein components can cycle continuously between speckles and other nuclear locations, including active transcription sites. Studies on the composition, structure and behaviour of speckles have provided a model for understanding the functional compartmentalization of the nucleus and the organization of the gene-expression machinery.

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Figure 1: Speckles form in the interchromatin space.
Figure 2: Immuno-electron microscopic localization of pre-mRNA splicing factors.
Figure 3: Modulation of transcription affects speckle organization.
Figure 4: The speckle cell cycle.
Figure 5: A 'regulated-exchange' model accounts for the dynamics of nuclear speckles.

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Acknowledgements

We thank members of the Lamond group, and K.V. Prasanth and P. Sacco-Bubulya in the Spector group for their helpful comments. We also appreciate the comments of S. Fakan, J. Gall, G. Matera and J. Swedlow. We thank A. Fox and Y. Wah Lam (University of Dundee, UK) for their help in preparing figures 1 and 3, and P. Sacco-Bubulya (Cold Spring Harbor Laboratory) for providing figure 4. A. I. L. is a Wellcome Trust Principal Research Fellow. D. L. S. is funded by the National Institute of General Medical Sciences/ National Institutes of Health.

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DATABASES

Interpro

POZ-domain

Locus Link

PP1

PSP1

Swiss-Prot

Cdk9

cyclin-T1

CLK/STY

eIF4E

FBI-1

GFP

HMG-17

lamin A

PRP4

SRPK1

FURTHER INFORMATION

Angus I. Lamond's laboratory

David Spector's laboratory

Glossary

SPECKLE

An irregularly shaped nuclear domain that is visualized by immunofluorescence microscopy, typically by using anti-splicing-factor antibodies. Usually 25–50 speckles are observed per interphase mammalian nucleus.

PARASPECKLE

A subnuclear structure that is distinct from speckles. Typically, 10–20 paraspeckles are present in the interchromatin nucleoplasmic space, and they are often located adjacent to speckles. So far, three proteins — paraspeckle proteins 1 and 2 and p54/nrb — have been localized to these nuclear domains.

CAJAL BODY

A nuclear structure that contains newly assembled small nuclear ribonucleoprotein particles that are involved in pre-messenger RNA splicing, and small nucleolar ribonucleoprotein particles that are involved in ribosomal RNA processing. Also contains Cajal-body-specific guide RNAs. Cajal bodies are usually identified as foci labelled with antibodies against the autoantigen p80 coilin.

GEMS

'Gemini of Cajal bodies' are nuclear structures that are usually localized either coincident with or adjacent to Cajal bodies, depending on the cell line examined. Gems are characterized by the presence of the 'survival of motor neurons' (SMN) protein.

PROMYELOCYTIC LEUKAEMIA (PML) BODY

A subnuclear structure that is also known as nuclear domain 10, promyelocytic leukaemia oncogenic domain or Kr body. These bodies are characterized by the presence of the promyelocytic leukaemia protein and there are typically 10–30 per nucleus.

INTERCHROMATIN GRANULE CLUSTER

(IGC). A structure seen by electron microscopy that is equivalent to the speckles that are seen by fluorescence microscopy. Each IGC is composed of a series of particles, 20–25 nm in diameter, that seem to be connected in places by a thin fibril.

PERICHROMATIN FIBRILS

Fibrils observed by the electron microscope that are detected at transcription sites and shown to coincide with the incorporation of tritiated-uridine or 5-bromouridine 5′-trisphosphate, indicating that they are nascent transcripts.

INTERCHROMATIN-GRANULE-ASSOCIATED ZONE

A region that is adjacent to interchromatin granule clusters, which contains U1, but not U2, small nuclear RNAs.

SR PROTEINS

A family of pre-messenger RNA splicing factors that are characterized by repeats of arginine–serine dipeptides at their carboxyl termini.

SNURPOSOME

A nuclear structure, identified in amphibian oocytes, that contains splicing small nuclear ribonucleoprotein particles. Three classes — known as A, B and C snurposomes — have been defined, and they differ in their composition. B snurposomes are most closely related to speckles in their composition, and could represent oocyte forms of the speckles that are found in somatic-cell nuclei.

CELLULARIZATION

The transition from a syncytium to distinct cells which occurs at the fourteenth round of cell division in the Drosophila melanogaster embryo.

CLK/STY

A kinase family, the members of which are characterized by having the serine residues in the arginine–serine domain of SR proteins as their primary substrates.

PRP4

A kinase that localizes to nuclear speckles and interacts with CLK/STY, as well as several proteins that are involved in pre-mRNA splicing (SF2/ASF, U5 snRNP) and chromatin remodelling (BRG1, N-CoR deacetylase complexes).

PSKH1

A human kinase that is localized to nuclear speckles but that does not directly interact with SR proteins.

MITOTIC INTERCHROMATIN GRANULES

(MIGS). The speckles (interchromatin granule clusters) that form in the cytoplasm of cells undergoing mitosis, and that increase in number from metaphase to telophase.

REGULATED-EXCHANGE MODEL

A model proposed in this review to account for the basic principles of speckle formation and their dynamic properties.

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Lamond, A., Spector, D. Nuclear speckles: a model for nuclear organelles. Nat Rev Mol Cell Biol 4, 605–612 (2003). https://doi.org/10.1038/nrm1172

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