| Structural highlights
Function
[SATB1_HUMAN] Crucial silencing factor contributing to the initiation of X inactivation mediated by Xist RNA that occurs during embryogenesis and in lymphoma (By similarity). Binds to DNA at special AT-rich sequences, the consensus SATB1-binding sequence (CSBS), at nuclear matrix- or scaffold-associated regions. Thought to recognize the sugar-phosphate structure of double-stranded DNA. Transcriptional repressor controlling nuclear and viral gene expression in a phosphorylated and acetylated status-dependent manner, by binding to matrix attachment regions (MARs) of DNA and inducing a local chromatin-loop remodeling. Acts as a docking site for several chromatin remodeling enzymes (e.g. PML at the MHC-I locus) and also by recruiting corepressors (HDACs) or coactivators (HATs) directly to promoters and enhancers. Modulates genes that are essential in the maturation of the immune T-cell CD8SP from thymocytes. Required for the switching of fetal globin species, and beta- and gamma-globin genes regulation during erythroid differentiation. Plays a role in chromatin organization and nuclear architecture during apoptosis. Interacts with the unique region (UR) of cytomegalovirus (CMV). Alu-like motifs and SATB1-binding sites provide a unique chromatin context which seems preferentially targeted by the HIV-1 integration machinery. Moreover, HIV-1 Tat may overcome SATB1-mediated repression of IL2 and IL2RA (interleukin) in T-cells by binding to the same domain than HDAC1. Delineates specific epigenetic modifications at target gene loci, directly up-regulating metastasis-associated genes while down-regulating tumor-suppressor genes. Reprograms chromatin organization and the transcription profiles of breast tumors to promote growth and metastasis.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]
Publication Abstract from PubMed
Phosphorothioate modification is commonly introduced into therapeutic oligonucleotides, typically as a racemic mixture in which either of the two non-bridging phosphate oxygens is replaced by sulfur, which frequently increases affinities with proteins. Here, we used isothermal titration calorimetry and X-ray crystallography to investigate the thermodynamic and structural properties of the interaction between the primary DNA-binding domain (CUTr1) of transcription factor SATB1 and dodecamer DNAs with racemic phosphorothioate modifications at the six sites known to contact CUTr1 directly. For both the modified and unmodified DNAs, the binding reactions were enthalpy-driven at a moderate salt concentration (50 mM NaCl), while being entropy-driven at higher salt concentrations with reduced affinities. The phosphorothioate modifications lowered this susceptibility to salt, resulting in a significantly enhanced affinity at a higher salt concentration (200 mM NaCl), although only some DNA molecular species remained interacting with CUTr1. This was explained by unequal populations of the two diastereomers in the crystal structure of the complex of CUTr1 and the phosphorothioate-modified DNA. The preferred diastereomer formed more hydrogen bonds with the oxygen atoms and/or more hydrophobic contacts with the sulfur atoms than the other, revealing the origins of the enhanced affinity.
Enhanced affinity of racemic phosphorothioate DNA with transcription factor SATB1 arising from diastereomer-specific hydrogen bonds and hydrophobic contacts.,Yamasaki K, Akutsu Y, Yamasaki T, Miyagishi M, Kubota T Nucleic Acids Res. 2020 Mar 18. pii: 5809661. doi: 10.1093/nar/gkaa170. PMID:32187371[19]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Dickinson LA, Dickinson CD, Kohwi-Shigematsu T. An atypical homeodomain in SATB1 promotes specific recognition of the key structural element in a matrix attachment region. J Biol Chem. 1997 Apr 25;272(17):11463-70. PMID:9111059
- ↑ de Belle I, Cai S, Kohwi-Shigematsu T. The genomic sequences bound to special AT-rich sequence-binding protein 1 (SATB1) in vivo in Jurkat T cells are tightly associated with the nuclear matrix at the bases of the chromatin loops. J Cell Biol. 1998 Apr 20;141(2):335-48. PMID:9548713
- ↑ Case SS, Huber P, Lloyd JA. The gammaPE complex contains both SATB1 and HOXB2 and has positive and negative roles in human gamma-globin gene regulation. DNA Cell Biol. 1999 Nov;18(11):805-17. PMID:10595394 doi:10.1089/104454999314809
- ↑ Galande S, Dickinson LA, Mian IS, Sikorska M, Kohwi-Shigematsu T. SATB1 cleavage by caspase 6 disrupts PDZ domain-mediated dimerization, causing detachment from chromatin early in T-cell apoptosis. Mol Cell Biol. 2001 Aug;21(16):5591-604. PMID:11463840 doi:10.1128/MCB.21.16.5591-5604.2001
- ↑ Yasui D, Miyano M, Cai S, Varga-Weisz P, Kohwi-Shigematsu T. SATB1 targets chromatin remodelling to regulate genes over long distances. Nature. 2002 Oct 10;419(6907):641-5. PMID:12374985 doi:10.1038/nature01084
- ↑ Cai S, Han HJ, Kohwi-Shigematsu T. Tissue-specific nuclear architecture and gene expression regulated by SATB1. Nat Genet. 2003 May;34(1):42-51. PMID:12692553 doi:10.1038/ng1146
- ↑ Wen J, Huang S, Rogers H, Dickinson LA, Kohwi-Shigematsu T, Noguchi CT. SATB1 family protein expressed during early erythroid differentiation modifies globin gene expression. Blood. 2005 Apr 15;105(8):3330-9. Epub 2004 Dec 23. PMID:15618465 doi:10.1182/blood-2004-08-2988
- ↑ Kumar PP, Purbey PK, Ravi DS, Mitra D, Galande S. Displacement of SATB1-bound histone deacetylase 1 corepressor by the human immunodeficiency virus type 1 transactivator induces expression of interleukin-2 and its receptor in T cells. Mol Cell Biol. 2005 Mar;25(5):1620-33. PMID:15713622 doi:25/5/1620
- ↑ Sun Y, Wang T, Su Y, Yin Y, Xu S, Ma C, Han X. The behavior of SATB1, a MAR-binding protein, in response to apoptosis stimulation. Cell Biol Int. 2006 Mar;30(3):244-7. Epub 2005 Dec 27. PMID:16377216 doi:10.1016/j.cellbi.2005.10.025
- ↑ Pavan Kumar P, Purbey PK, Sinha CK, Notani D, Limaye A, Jayani RS, Galande S. Phosphorylation of SATB1, a global gene regulator, acts as a molecular switch regulating its transcriptional activity in vivo. Mol Cell. 2006 Apr 21;22(2):231-43. PMID:16630892 doi:10.1016/j.molcel.2006.03.010
- ↑ Kumar PP, Mehta S, Purbey PK, Notani D, Jayani RS, Purohit HJ, Raje DV, Ravi DS, Bhonde RR, Mitra D, Galande S. SATB1-binding sequences and Alu-like motifs define a unique chromatin context in the vicinity of human immunodeficiency virus type 1 integration sites. J Virol. 2007 Jun;81(11):5617-27. Epub 2007 Mar 21. PMID:17376900 doi:10.1128/JVI.01405-06
- ↑ Kumar PP, Bischof O, Purbey PK, Notani D, Urlaub H, Dejean A, Galande S. Functional interaction between PML and SATB1 regulates chromatin-loop architecture and transcription of the MHC class I locus. Nat Cell Biol. 2007 Jan;9(1):45-56. Epub 2006 Dec 17. PMID:17173041 doi:10.1038/ncb1516
- ↑ Han HJ, Russo J, Kohwi Y, Kohwi-Shigematsu T. SATB1 reprogrammes gene expression to promote breast tumour growth and metastasis. Nature. 2008 Mar 13;452(7184):187-93. doi: 10.1038/nature06781. PMID:18337816 doi:10.1038/nature06781
- ↑ Gong H, Wang Z, Zhao GW, Lv X, Wei GH, Wang L, Liu DP, Liang CC. SATB1 regulates beta-like globin genes through matrix related nuclear relocation of the cluster. Biochem Biophys Res Commun. 2009 May 22;383(1):11-5. doi:, 10.1016/j.bbrc.2009.03.122. Epub 2009 Mar 28. PMID:19332023 doi:10.1016/j.bbrc.2009.03.122
- ↑ Cai R, Xu W, Dai B, Cai X, Xu R, Lu J. SATB1 binds an intronic MAR sequence in human PI3kgamma in vitro. Mol Biol Rep. 2010 Mar;37(3):1461-5. doi: 10.1007/s11033-009-9538-y. Epub 2009, May 10. PMID:19430959 doi:10.1007/s11033-009-9538-y
- ↑ Purbey PK, Singh S, Notani D, Kumar PP, Limaye AS, Galande S. Acetylation-dependent interaction of SATB1 and CtBP1 mediates transcriptional repression by SATB1. Mol Cell Biol. 2009 Mar;29(5):1321-37. doi: 10.1128/MCB.00822-08. Epub 2008 Dec, 22. PMID:19103759 doi:10.1128/MCB.00822-08
- ↑ Wang L, Di LJ, Lv X, Zheng W, Xue Z, Guo ZC, Liu DP, Liang CC. Inter-MAR association contributes to transcriptionally active looping events in human beta-globin gene cluster. PLoS One. 2009;4(2):e4629. doi: 10.1371/journal.pone.0004629. Epub 2009 Feb 27. PMID:19247486 doi:10.1371/journal.pone.0004629
- ↑ Yamasaki K, Akutsu Y, Yamasaki T, Miyagishi M, Kubota T. Enhanced affinity of racemic phosphorothioate DNA with transcription factor SATB1 arising from diastereomer-specific hydrogen bonds and hydrophobic contacts. Nucleic Acids Res. 2020 Mar 18. pii: 5809661. doi: 10.1093/nar/gkaa170. PMID:32187371 doi:http://dx.doi.org/10.1093/nar/gkaa170
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