PML is a tumour suppressor protein that typically localizes to and is necessary for the formation of nuclear macromolecular structures called promyelocytic leukaemia nuclear bodies (PML-NBs).
PML-NBs are discrete nuclear foci of 0.2–1.0 μm in diameter that are present in most mammalian cell nuclei. They typically number 1–30 bodies per nucleus, depending on the cell type, cell-cycle phase and differentiation stage.
PML-NBs are dynamic structures that undergo significant changes in number, size and position during cell-cycle progression and in response to cellular stresses such as DNA damage and induction of senescence.
PML-NBs can be found near other nuclear organelles, such as Cajal bodies, and associate with genomic regions that are transcriptionally active. In addition, a specific association has been shown with specific chromosomal loci.
Many proteins transiently and constitutively localize to PML-NBs. As a result, PML-NBs have been implicated in the regulation of diverse cellular functions including induction of apoptosis and senescence, inhibition of proliferation, maintenance of genomic stability and antiviral responses.
Recent data suggest that PML-NBs are heterogeneous structures and that different PML-NBs may regulate specific cellular functions according to their protein composition, their position in the nucleus and their mobility.
The promyelocytic leukaemia (PML) tumour suppressor protein epitomizes the PML-nuclear body (PML-NB) and is crucially required for the proper assembly of this macromolecular nuclear structure. Unlike other, more specialized subnuclear structures such as Cajal and Polycomb group bodies, PML-NBs are functionally promiscuous and have been implicated in the regulation of diverse cellular functions. PML-NBs are dynamic structures that favour the sequestration and release of proteins, mediate their post-translational modifications and promote specific nuclear events in response to various cellular stresses. Recent data suggest that PML-NBs may be heterogeneous in composition, mobility and function.
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We are grateful to L. DiSantis for critical reading of the manuscript and all members of the Pandolfi laboratory for insightful comments and discussion. This work was supported by the National Institutes of Health.
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- Nuclear matrix
A network of nuclear proteins that provides a structural framework for organizing chromatin.
- Cajal body
A spherical organelle found in the nucleus of proliferative or transcriptionally active cells. It is involved in the biogenesis and trafficking of RNA–protein complexes that regulate RNA processing, and is named after Santiago Ramon y Cajal who described the organelle in 1903.
- Splicing speckle
A storage site of mRNA splicing factors.
- Immunofluorescence in situ hybridization
A technique that combines immunocytochemistry with fluorescence in situ hybridization to visualize the association between proteins and DNA.
- Major histocompatibility complex
(MHC). A family of cellular antigens that allow the immune system to distinguish self from non-self, encoded by a large genomic region in higher vertebrates.
- Acute promyelocytic leukaemia
(APL). A subtype of acute myeloid leukaemia that is characterized by the accumulation of immature granulocytes called promyelocytes.
A soluble glycoprotein (cytokine) that is produced by cells of the immune system and regulates antiviral and immunological responses by inducing the expression of a series of genes.
- Nuclear localization signal
(NLS). A short stretch of positively charged amino acids that mediates the transport of proteins into the nucleus.
A zinc-binding protein domain defined by a series of conserved Cys and His residues.
- Coiled-coil domain
A protein structural domain that mediates subunit oligomerization. Coiled coils contain 2–5 α-helices that twist around each other to form a supercoil.
- Arsenic trioxide
A chemotherapeutic compound that is used to treat patients with acute promyelocytic leukaemia.
- E3 ubiquitin ligase
The third enzyme in a series — the first two are designated E1 and E2 — that is responsible for ubiquitylation of target proteins. E3 enzymes provide platforms for binding E2 enzymes and specific substrates, thereby coordinating ubiquitylation of the selected substrates.
An evolutionarily conserved post-translational modification whereby the small ubiquitin-like modifier (SUMO) protein becomes covalently conjugated to a subset of proteins by the concerted action of an E1 activating enzyme, an E2 conjugating enzyme and an E3 ligase.
- SUMO protease
An enzyme that catalyses the removal of SUMO moieties from proteins by cleaving isopeptide bonds.
- RING domain
A Cys-rich tandem zinc-finger domain of 40–60 amino acids that is often found in E3 ubiquitin ligases.
- SUMO E3 ligase
A protein that enhances the conjugation of SUMO to target proteins by the SUMO-conjugating UBC9 enzyme.
- Time-lapse microscopy
Microscopy in which the same cell is photographed at regular time intervals over several hours.
- Fluorescence recovery after photobleaching
(FRAP). A technique that measures the rate of recovery of fluorescence owing to the movement of a fluorescent marker into an area of the cell after that area has been rendered non-fluorescent by photobleaching.
- Centromeric region
The part of a chromosome that is attached to the spindle during nuclear division.
A specialized structure at the ends of a chromosome that contains repetitive DNA sequences. Telomere length declines with each cell division.
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Bernardi, R., Pandolfi, P. Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat Rev Mol Cell Biol 8, 1006–1016 (2007). https://doi.org/10.1038/nrm2277
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