Nuclear Compartments: PML body

NPD Nuclear Compartments: PML BODY

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The average mammalian cells contains 10-30 PML nuclear bodies (also referred to as PML NBs, ND10, PODs, SP-100 and Kr bodies). PML bodies have been associated with just about every nuclear function possible including; transcription, DNA repair, viral defence, stress, cell cycle regulation, proteolysis and apoptosis, and there is still vigorous debate about their true biological function(s) (Borden, 2002 ; Dellaire & Bazzett-Jones, 2004; Ching et al., 2005;Bernardi & Pandolfi, 2007 )

PML protein

PML bodies are defined by the presence of the PML protein, first identified by its fusion to the retinoic acid receptor alpha (RARa) in translocation t(15,17) associated acute promyelocytic leukaemia (APL). PML protein is essential for the formation of PML NBs, and when it is absent, or its RING fingers mutated, PML NBs are disrupted. Study of PML protein is complicated by its multiple isoforms, some of which are cytoplasmic, and by its modification by SUMO-1. PML is not essential for viability: PML-/- mice appear normal, but they do have a perturbed apoptotic response to cellular insults such as irradiation (Wang et al., 1998). PML is a member of the RBCC family of proteins.

PML bodies, post translational modification, and disease

Cells from APL individuals have fragmented PML bodies. Treatment with all-trans-retinoic acid (ATRA) allows these bodies to reform and, remarkably, this correlates with remission from disease (Weis et al., 1994). Arsenic trioxide (As2O3) is also effective in the treatment of APL, and it restores PML NBs. As2O3 enhances sumolation of PML, and so triggers the ubiquitination by RNF4, and the subsequent proteasome-dependent degradation of PML and PML/RARalpha (Lallemand-Breitenbach et al., 2008; Tatham et al., 2008). PML bodies are also targeted by a number of RNA and DNA viruses. Recently, it has been shown that structures resembling PML NBs form de novo, and in association with viral genome complexes, during the initial stages of herpes simplex virus type 1 (HSV-1) infection (Everett and Murray, 2005). The initial sites of transcription and development of DNA replication centres of DNA viruses are frequently juxtaposed to PML bodies, and at late stages of infection PML NBs can be disrupted (reviewed in Everett, 2001) . In spinocerebellar ataxia, mutant ataxins with large-expanded polyglutamine tracts first form nuclear inclusions that accumulate PML and other PML NB proteins. This eventually leads to the disruption of PML NBs (Dovey et al., 2004).

Dynamics of PML bodies and associated proteins

At least three classes of PML nuclear body can be distinguished by their types of movement within living cells. One of these classes shows metabolic-energy-dependent movement within the nucleus (Muratani et al., 2002). As well as viruses, DNA alkylating agents can cause the dispersal of PML NB proteins(Conlan et al., 2004). Inhibition of proteasome-dependent protein degradation by the drug MG132 also redistributes PML, Sp100, and SUMO-1 out of PML NBs and into the nucleolus (Mattsson et al., 2001). SUMO-1 modification of both PML and Sp100 may regulate the dynamics of protein localisation within PML bodies. For example, although SUMO-1 modification of the PML protein is not required for nuclear body formation, the accumulation of many other PML body-associated proteins (e.g. CBP, Daxx, Sp100) within these structures does appear to require the sumolation of PML. Overexpression of the SUMO-1 protease SENP2, redistributes several PML NB proteins (reviewed in Dellaire and Bazett-Jones, 2004) .

PML bodies and transcription

PML has been implicated in both transcriptional activation and repression, largely through the concentration of transcription factors and chromatin modifying enzymes in PML NBs. However, these suggestions have to be considered alongside the very moderate phenotype of PML-/- mice (Wang et al., 1998). Some very transcriptionally active regions of the human genome do associate frequently with PML NBs. However, the PML NBs themselves are not the sites of actual transcription of genes from these regions and RNAi-mediated knockdown of PML does not perturb the expression of these genes (Wang et al., 2004).

PML bodies as nuclear waste disposal sites?

One postulated function of PML NBs is as nuclear scavengers for large concentrations of foreign or misfolded proteins. This would be consistent with their accumulation around viral genomes (see above), and at high concentrations of GFP-tagged bacterial lac repressor protein (Tsukamoto et al., 2000). The presence of proteosomes next to PML NBs is also consistent with a role in protein degradation (Lallemand-Breitenbach et al., 2001).

PML bodies, DNA repair, apoptosis and telomere maintenance

PML bodies might also serve as sites for the post-translational modification of proteins. For example, the concentration of p53, CBP and HIPK2 in PML NBs contributes to the DNA damage-induced phosphorylation and acetylation of p53 (reveiwed in Dellaire and Bazett-Jones, 2004). There is regulated movement of several DNA repair proteins in and out of PML NBs in respinse to DNA damage.

PML NBs are also involved in the alternative mechanism of telomere maintenance (ALT) that can occur in telomerase -ve cells. In ALT cells a subset of PML NBs (ALT-associated PML NBs) co-localise with telomeres , telomere associated proteins and proteins involved in DNA repair and recombination (Grobelny et al., 2000).

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Other Internet Resources on PML bodies:

· Borden laboratory website

· PML body image database from www.cellnucleus.com

· Human cytomegalovirus (HCMV) and PML home page of Richard Caswell.

REFERENCES

Bernardi, R & Pandolfi, PP. (2007). Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat. Rev. Mol. Cell Biol.. 8:1006 -1016.

Borden, KLB. (2002) Pondering the Promyelocytic leukemia protein (PML) puzzle: possible functions for PML nuclear bodies. Mol. Cell Biol. 22:5259-5269.

Ching, R.W., Dellaire, G., Eskiw, C.H. and Bazett-Jones, D.P. (2005) PML bodies: a meeting place for genomic loci? J. Cell Sci. 118:847-854.

Conlan LA, McNees CJ, Heierhorst J. (2004) Proteasome-dependent dispersal of PML nuclear bodies in response to alkylating DNA damage. Oncogene. 23:307-310.

Dellaire G, and Bazett-Jones, DP. (2004) PML nuclear bodies: dynamic sensors of DNA damage and cellular stress. Bioessays. 26:963-977.

Dovey CL, Varadaraj A, Wyllie AH, Rich T. (2004) Stress responses of PML nuclear domains are ablated by ataxin-1 and other nucleoprotein inclusions. J. Pathol. 203:877-883.

Everett, R.D. (2001) DNA viruses and viral proteins that interact with PML nuclear bodies. Oncogene 20:7266-7273

Everett, R.D and Murray, J. (2005) ND10 components relocate to sites associated with herpes simplex virus type 1 nucleoprotein complexes during virus infection. J. Virol. 79:5078-5089.

Grobelny JV, Godwin AK, Broccoli D. (2000) ALT-associated PML bodies are present in viable cells and are enriched in cells in the G(2)/M phase of the cell cycle J. Cell Sci. 113:4577-4585.

Lallemand-Breitenbach V, Jeanne M, Benhenda S, Nasr R, Lei M, Peres L, Zhou J, Zhu J, Raught B, de Thé H (2008) Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat Cell Biol. 10:547-555.

Mattsson K, Pokrovskaja K, Kiss C, Klein G, Szekely L. (2001) Proteins associated with the promyelocytic leukemia gene product (PML)-containing nuclear body move to the nucleolus upon inhibition of proteasome-dependent protein degradation. PNAS 98:1012-1017.

Tatham MH, Geoffroy MC, Shen L, Plechanovova A, Hattersley N, Jaffray EG, Palvimo JJ, Hay RT. 2008. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation Nat Cell Biol. 10:538-546.

Muratani M, Gerlich D, Janicki SM, Gebhard M, Eils R, Spector DL. (2002) Metabolic-energy-dependent movement of PML bodies within the mammalian cell nucleus. Nat. Cell Biol. 4:106-110.

Tsukamoto T, Hashiguchi N, Janicki SM, Tumbar T, Belmont AS, Spector DL (2000) Visualization of gene activity in living cells. Nat. Cell Biol. 2:871-878.

Wang J, Shiels C, Sasieni P, Wu PJ, Islam SA, Freemont PS, Sheer D. (2004) Promyelocytic leukemia nuclear bodies associate with transcriptionally active genomic regions. J. Cell Biol. 164:515-526.

Wang ZG, Ruggero D, Ronchetti S, Zhong S, Gaboli M, Rivi R, Pandolfi PP. (1998) PML is essential for multiple apoptotic pathways. Nat. Genet. 20:266-272

Weis K, Rambaud S, Lavau C, Jansen J, Carvalho T, Carmo-Fonseca M, Lamond A, Dejean A. (1994) Retinoic acid regulates aberrant nuclear localization of PML-RAR alpha in acute promyelocytic leukemia cells. Cell. 76:345-356