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From CellBiology

Nuclear Body Protein SP100

History

1984 Discovered as targets of autoantibodies in patients suffering from the autoimmune disease primary biliary cirrhosis.

1990 After the discovery, the protein was named SP100 (speckled protein of 100 kDa) after forming a 'speckle' shape in the nucleus by using sera from the patients.

1991 Identification of novel nuclear domain as a dot pattern distributed throughtout nucleoplasm. It was located distinctly from kinetochores, centromeres, sites of mRNA processing and tRNA synthesis, nuclear bodies, and chromosomes. [1]

1994 Specific defected protein, "fusion of PML/RARα protein" was recognised to play major role in acute promyelocytic leukemia (APL) molecular mechanism. This protein contained an antigenic site that was not present in the normal pattern of nucleus and had cytotoxic activity that can distrupt the expression of other PML/RARα protein. [2]

1998 Novel protein motif, the HSR domain, was discovered , within this ND targeting/dimerisation domain.

2001 The fourth splice variant, SP100C was found from an isolated a partial cDNA of human liver.

Overview of SP100 Protein

SP100 protein was first identified as a nuclear autoimmune antigen in the bile duct of patient suffering from autoimmune disease primary biliary cirrhosis. It was named after the weight and shape of 100-kDa Speckled protein.

Function

SP100 is part of the components in the nuclear body. They involve during the immune response by regulating the transcription process. Such work is done in conjunction with PML nuclear bodies whereby PML regulates the transcriptional activity and SP100 work to repress the action. The bodies is also responsible for delivering mRNA across the nucleus. [3]. Interferons (IFNs), a cytokine released during immune response can upregulate the transcription of SP100, especially during the cellular antigen response against virus. This transcription process also plays roles in autoimmunity and oncogenesis [4]. Although the exact function of this protein is not yet clear, it was predicted to involve in the function of ND targeting, nuclear import, nuclear SUMOylation, and protein-protein interaction. [5]

Structure

3D molecular structure of SP100 protein.

SP100 and nuclear dots

The SP100 autoantigen and promyelocytic leukaemia proteins are often described as part of the components in subnuclear domain that makes nuclear dots (ND) or known as PML-SP100 nuclear bodies (NBs). They range from the size 0.1 to 1.0 mm in nucleoplasm. The disruption of this ubiquitous structures can cause acute promyelocytic leukemia (APL) and in DNA virus infection whereby the virus encode a protein and distrupt the NBs. SP100 protein and PML are covalently modified by the small ubiquitin-related protein SUMO-1. The modification requires nuclear localisation signal (NLS) and involves some lysine residue.


SP100 is also known to bind and interact with the members of heterochromatin protein 1 (HP1) families of non-histone chromosomal proteins. This protein present targets for the process of transcription, DNA replication and repair. Combined with one of its splice variants, HMG, SP100-HMG have the DNA-binding potential under a protein family of the high mobility group-1 (HMG-1). When all the three presents, SP100, HP1, and SP100-HMG, they can serve the function of transcriptional activity by attaching to the promotor. This type of SP100 were found to be concentrated within PML/SP100 nuclear bodies. [6].


Splice Variants

As a protein family, Sp100 has subfamilies such as Sp110, Sp140/LYSp100 and the autoimmune regulator protein (AIRE) that share an amino-terminus HSR (homogeneously staining region) domain [7]. SP100 proteins also have different splice variant forms that contain distinct subnuclear localisation areas in PML-SP100 NB components [8]. These splice variants, are the one that could be modified covalently by SUMO-1 as well as conducting the activities at the chromatin level. They are also responsible for the structural integrity of NBs.

There are four different types of splice variants in SP100 :


Four different splice variants

SP100A

It contains 480 amino acids - the most abundant form. The A domain includes HSR and HP1. It is the main and exclusive constituent of PML NBs in the form of autoantigen. It can stimulate transcription activation by ETS-1 and inhibits the process by Bright (B cell regulator of immunoglobulin heavy chain transcription) depending which protein they begin to interact with[9].

SP100-HMG

the large variant, contains extra functional domains such as a SAND domain and a HMG box processing a DNA-binding domain that can affect chromatin structure [10].

SP100B

SP100B, a binding domain required during gene repression, especially during viral infections. It is only found during cell stress and after it interacts with an interferon. With the addition of SAND and high mobility group (HMG) interaction domain that serve as a DNA binding domain. It can then regulate transcription from chromosomal genes such as AIRE-1 (autoimmune regulator 1) and NUDR (nuclear DEAF-1 related). In a study done by Wilcox, et.al (2005) [11], it was shown that SP100B plays roles during the repression from an activated promoter and represses basal promoter activity by inhibiting the transactivation of ICP4, hence repressing both promoters. The required domains for repression were predicted to lie on the C-terminal of B domain that contains HMG and SAND expression that interact with HP1 domain.

SP100C

a novel splice variant that is homology to chromatin-associated factors. It contains distinct domain consisting of PHD finger-bromodomain motif. The splice variants have differences in the domain compositions in carboxy termini yet all the four contain the same pattern in the amino-terminal domain. It has been speculated that this occurs so that they can carry on their functions separately, such as directing SP100 proteins at the NBs by N-terminal alone.


Current Research

A study done by Zhong (2007) shows that overexpression of SP100 protein is known to suppress alternative lengthening of telomeres (ALT), a condition whereby telomerase of immortalised human cells are maintained. SP100 and segregated MRE11/RAD50/NBS1 (MRN) form recombination protein complex, especially NBS1, that is required for ALT activition. Many factors could decrease the amount of MRN complex found in ALT cells and may result in inhibition of ALT-mediated telomere process. This evidence has been seen in ALT-associated promyelocytic leukemia bodies and decreased telomere length. [12]

SP100 protein exact mechanism remains elusive. This will require more research in the future since the protein has versatile profiles that often can lead to the formation of human disease such as promyelocytic leukemia.

Reference

  1. Ascoli, C., & Maul, G. (1991). Identification of a novel nuclear domain. Journal of Cell Biology, 112(5), 785-795.
  2. Grignani, F., Fagioli, M., Alcalay, M., Longo, L., Pandolfi, P., Donti, E., et al. (1994). Acute promyelocytic leukemia: from genetics to treatment. Blood, 83(1), 10.
  3. Zhong, S., Salomoni, P., & Pandolfi, P. (2000). The transcriptional role of PML and the nuclear body. Nature cell biology, 2(5), E85-E90.
  4. Seeler, J., Marchio, A., Losson, R., Desterro, J., Hay, R., Chambon, P., et al. (2001). Common properties of nuclear body protein SP100 and TIF1a chromatin factor: role of SUMO modification. Molecular and Cellular Biology, 21(10), 3314-3324.
  5. Sternsdorf, T., Jensen, K., Reich, B., & Will, H. (1999). The nuclear dot protein sp100, characterization of domains necessary for dimerization, subcellular localization, and modification by small ubiquitin-like modifiers. Journal of Biological Chemistry, 274(18), 12555-12566.
  6. Zhong, S., Salomoni, P., & Pandolfi, P. (2000). The transcriptional role of PML and the nuclear body. Nature cell biology, 2(5), E85-E90.
  7. Möller, A., Sirma, H., Hofmann, T., Staege, H., Gresko, E., Lüdi, K., et al. (2003). Sp100 is important for the stimulatory effect of homeodomain-interacting protein kinase-2 on p53-dependent gene expression. Oncogene, 22(54), 8731-8737.
  8. Seeler, J., Marchio, A., Losson, R., Desterro, J., Hay, R., Chambon, P., et al. (2001). Common properties of nuclear body protein SP100 and TIF1a chromatin factor: role of SUMO modification. Molecular and Cellular Biology, 21(10), 3314-3324.
  9. Wilcox, K., Sheriff, S., Isaac, A., & Taylor, J. (2005). SP100B is a repressor of gene expression. Journal of cellular biochemistry, 95(2).
  10. Zhong, S., Salomoni, P., & Pandolfi, P. (2000). The transcriptional role of PML and the nuclear body. Nature cell biology, 2(5), E85-E90.
  11. Wilcox, K., Sheriff, S., Isaac, A., & Taylor, J. (2005). SP100B is a repressor of gene expression. Journal of cellular biochemistry, 95(2).
  12. Zhong, Z., Jiang, W., Cesare, A., Neumann, A., Wadhwa, R., & Reddel, R. (2007). Disruption of telomere maintenance by depletion of the MRE11/RAD50/NBS1 complex in cells that use alternative lengthening of telomeres. Journal of Biological Chemistry, 282(40), 29314.