4hpl

Structural highlights

Disease

[BCOR_HUMAN] Defects in BCOR are the cause of microphthalmia syndromic type 2 (MCOPS2) [MIM:300166]. Microphthalmia is a clinically heterogeneous disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). In many cases, microphthalmia/anophthalmia occurs in association with syndromes that include non-ocular abnormalities. MCOPS2 is a very rare multiple congenital anomaly syndrome characterized by eye anomalies (congenital cataract, microphthalmia, or secondary glaucoma), facial abnormalities (long narrow face, high nasal bridge, pointed nose with cartilages separated at the tip, cleft palate, or submucous cleft palate), cardiac anomalies (atrial septal defect, ventricular septal defect, or floppy mitral valve) and dental abnormalities (canine radiculomegaly, delayed dentition, oligodontia, persistent primary teeth, or variable root length).^[1]

Function

[BCOR_HUMAN] Transcriptional corepressor. May specifically inhibit gene expression when recruited to promoter regions by sequence specific DNA-binding proteins such as BCL6 and MLLT3. This repression may be mediated at least in part by histone deacetylase activities which can associate with this corepressor. Involved in the repression of TFAP2A; impairs binding of BCL6 and KDM2B to TFAP2A promoter regions. Via repression of TFAP2A acts as a negative regulator of osteo-dentiogenic capacity in adult stem cells; the function implies inhibition of methylation on histone H3 'Lys-4' (H3K4me3) and 'Lys-36' (H3K36me2).^{[2] [3] [4] [5]} [PCGF1_HUMAN] Component of the Polycomb group (PcG) multiprotein BCOR complex, a complex required to maintain the transcriptionally repressive state of some genes, such as BCL6 and the cyclin-dependent kinase inhibitor, CDKN1A. Transcriptional repressor that may be targeted to the DNA by BCL6; this transcription repressor activity may be related to PKC signaling pathway. Represses CDKN1A expression by binding to its promoter, and this repression is dependent on the retinoic acid response element (RARE element). Promotes cell cycle progression and enhances cell proliferation as well. May have a positive role in tumor cell growth by down-regulating CDKN1A. Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility.^{[6] [7] [8]}

References

1. ↑ Ng D, Thakker N, Corcoran CM, Donnai D, Perveen R, Schneider A, Hadley DW, Tifft C, Zhang L, Wilkie AO, van der Smagt JJ, Gorlin RJ, Burgess SM, Bardwell VJ, Black GC, Biesecker LG. Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR. Nat Genet. 2004 Apr;36(4):411-6. Epub 2004 Mar 7. PMID:15004558 doi:10.1038/ng1321
2. ↑ Huynh KD, Fischle W, Verdin E, Bardwell VJ. BCoR, a novel corepressor involved in BCL-6 repression. Genes Dev. 2000 Jul 15;14(14):1810-23. PMID:10898795
3. ↑ Ng D, Thakker N, Corcoran CM, Donnai D, Perveen R, Schneider A, Hadley DW, Tifft C, Zhang L, Wilkie AO, van der Smagt JJ, Gorlin RJ, Burgess SM, Bardwell VJ, Black GC, Biesecker LG. Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR. Nat Genet. 2004 Apr;36(4):411-6. Epub 2004 Mar 7. PMID:15004558 doi:10.1038/ng1321
4. ↑ Fan Z, Yamaza T, Lee JS, Yu J, Wang S, Fan G, Shi S, Wang CY. BCOR regulates mesenchymal stem cell function by epigenetic mechanisms. Nat Cell Biol. 2009 Aug;11(8):1002-9. doi: 10.1038/ncb1913. Epub 2009 Jul 5. PMID:19578371 doi:10.1038/ncb1913
5. ↑ Ghetu AF, Corcoran CM, Cerchietti L, Bardwell VJ, Melnick A, Prive GG. Structure of a BCOR corepressor peptide in complex with the BCL6 BTB domain dimer. Mol Cell. 2008 Feb 15;29(3):384-91. PMID:18280243 doi:10.1016/j.molcel.2007.12.026
6. ↑ Gong Y, Wang X, Liu J, Shi L, Yin B, Peng X, Qiang B, Yuan J. NSPc1, a mainly nuclear localized protein of novel PcG family members, has a transcription repression activity related to its PKC phosphorylation site at S183. FEBS Lett. 2005 Jan 3;579(1):115-21. PMID:15620699 doi:10.1016/j.febslet.2004.11.056
7. ↑ Gearhart MD, Corcoran CM, Wamstad JA, Bardwell VJ. Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets. Mol Cell Biol. 2006 Sep;26(18):6880-9. PMID:16943429 doi:26/18/6880
8. ↑ Gong Y, Yue J, Wu X, Wang X, Wen J, Lu L, Peng X, Qiang B, Yuan J. NSPc1 is a cell growth regulator that acts as a transcriptional repressor of p21Waf1/Cip1 via the RARE element. Nucleic Acids Res. 2006;34(21):6158-69. Epub 2006 Nov 6. PMID:17088287 doi:gkl834
9. ↑ Junco SE, Wang R, Gaipa JC, Taylor AB, Schirf V, Gearhart MD, Bardwell VJ, Demeler B, Hart PJ, Kim CA. Structure of the Polycomb Group Protein PCGF1 in Complex with BCOR Reveals Basis for Binding Selectivity of PCGF Homologs. Structure. 2013 Apr 2;21(4):665-71. doi: 10.1016/j.str.2013.02.013. Epub 2013 Mar, 21. PMID:23523425 doi:http://dx.doi.org/10.1016/j.str.2013.02.013