The primary function of the nucleolus is as the site of ribosome-subunit biogenesis in eukaryotic cells. The initial ribosomal RNA (rRNA) precursor is transcribed by RNA polymerase I and is subsequently processed and assembled with the many ribosomal proteins to form ribosome subunits, which are exported to the cytoplasm.
The nucleolus is a dynamic structure that disassembles when cells enter mitosis and reassembles following cell division. This involves a complex and highly regulated series of stepwise molecular assembly and disassembly pathways.
Nucleoli respond to changes in cellular growth rate and metabolic activity by altering rates of ribosome production, which indicates that they constantly receive and react to signalling events. Various proteins and activities have been shown to associate with the nucleolus specifically at different stages of the cell cycle, which suggests a role for nucleoli in regulating specific aspects of cell-cycle progression.
The nucleolus has been linked to several human diseases involving a range of different mechanisms. Multiple genetic disorders have been mapped to human genes that encode proteins that are known to associate with nucleoli, whereas many forms of cancer and viral infections affect nucleolar structure or the biogenesis of ribosomes.
As well as its role in coordinating the processing and maturation of rRNAs, several lines of evidence indicate that the nucleolus is also involved in the processing and/or maturation of additional classes of cellular ribonucleoproteins (RNPs), including the signal recognition particle and telomerase reverse transcriptase. This supports a role for the nucleolus as an important centre for RNP biogenesis.
The nucleolus is a distinct subnuclear compartment that was first observed more than 200 years ago. Nucleoli assemble around the tandemly repeated ribosomal DNA gene clusters and 28S, 18S and 5.8S ribosomal RNAs (rRNAs) are transcribed as a single precursor, which is processed and assembled with the 5S rRNA into ribosome subunits. Although the nucleolus is primarily associated with ribosome biogenesis, several lines of evidence now show that it has additional functions. Some of these functions, such as regulation of mitosis, cell-cycle progression and proliferation, many forms of stress response and biogenesis of multiple ribonucleoprotein particles, will be discussed, as will the relation of the nucleolus to human diseases.
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We are grateful to B. McStay for providing FISH images and D.P. Bazett-Jones for EF-TEM images. We thank Y. Wah Lam and other members of the Lamond group for advice and for providing images. A.I.L. is a Wellcome Trust Principal Research Fellow. F.-M.B. is supported by a fellowship from the Caledonian Research Foundation and S.V.K. by a fellowship from the Netherlands Organization for Scientific Research.
The authors declare no competing financial interests.
- Acrocentric chromosome
A chromosome with a centromere that is located near one end of the chromosome. Humans have five pairs of acrocentric chromosomes.
- Small nucleolar ribonucleoproteins
Nucleolar RNA–protein complexes that function in pre-ribosomal RNA processing.
- CENP proteins
Proteins that associate with the centromere, the region of a chromosome that is attached to the spindle during nuclear division.
- Chromosomal passenger protein
A protein that shares a characteristic pattern of association with chromatin in prophase, centromeres in metaphase and early anaphase, and the midzone and midbody in late anaphase and telophase, respectively.
- Cdc14 early anaphase release (FEAR) network
A signalling network in which the role for the protein phosphatase Cdc14 is key in the coordination of the multiple events that occur during anaphase, such as partitioning of the DNA, regulation of spindle stability, activation of microtubule forces and initiation of mitotic exit.
- Werner syndrome
A rare autosomal recessive disorder, characterized by the early development of various age-related diseases. The gene that is responsible for Werner syndrome (WRN) encodes a DNA helicase that is homologous to Escherichia coli RecQ.
- Bloom syndrome
An autosomal recessive disorder that is characterized by growth deficiency, unusual facial features, sun sensitivity, telangiectatic erythema, immunodeficiency and a predisposition to cancer. BLM, the gene that is mutated in Bloom syndrome, encodes a DNA helicase of the RECQ family.
- Rothmund–Thomson syndrome
(RTS). Patients exhibit chromosome fragility, skin and skeletal defects, cataracts and an increased predisposition to osteosarcoma. Some cases of RTS are caused by mutations in the DNA helicase gene RECQL4.
- Promyelocytic leukaemia nuclear body
A round nuclear structure that contains several proteins, including the promyelocytic leukaemia protein (PML). It is thought to be the site of recruitment of various proteins and might also have a role in gene transcription.
- Cajal body
A round nuclear structure that contains several proteins, including coilin and survival of motor neuron (SMN1). It is thought to be the site of small nuclear ribonucleoprotein assembly and small nuclear RNA maturation.
- Small nuclear RNPs
Nuclear RNA–protein complexes that combine with pre-mRNA and various proteins to form the spliceosomes.
- Signal recognition particle
A ribonucleoprotein complex that is responsible for the recognition of the N-terminal signal-peptide sequence on nascent proteins and for the proper targeting of proteins onto a receptor on the cytoplasmic face of the endoplasmic reticulum.
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Boisvert, FM., van Koningsbruggen, S., Navascués, J. et al. The multifunctional nucleolus. Nat Rev Mol Cell Biol 8, 574–585 (2007). https://doi.org/10.1038/nrm2184
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