| Structural highlights
Disease
[PHF8_HUMAN] Defects in PHF8 are the cause of mental retardation syndromic X-linked Siderius type (MRXSSD) [MIM:300263]. A disorder characterized by mild to borderline mental retardation with or without cleft lip/cleft palate.[1] [2] [3] [4] [5] [6] [7] [8] [9]
Function
[PHF8_HUMAN] Histone lysine demethylase with selectivity for the di- and monomethyl states that plays a key role cell cycle progression, rDNA transcription and brain development. Demethylates mono- and dimethylated histone H3 'Lys-9' residue (H3K9Me1 and H3K9Me2), dimethylated H3 'Lys-27' (H3K27Me2) and monomethylated histone H4 'Lys-20' residue (H4K20Me1). Acts as a transcription activator as H3K9Me1, H3K9Me2, H3K27Me2 and H4K20Me1 are epigenetic repressive marks. Involved in cell cycle progression by being required to control G1-S transition. Acts as a coactivator of rDNA transcription, by activating polymerase I (pol I) mediated transcription of rRNA genes. Required for brain development, probably by regulating expression of neuron-specific genes. Only has activity toward H4K20Me1 when nucleosome is used as a substrate and when not histone octamer is used as substrate. May also have weak activity toward dimethylated H3 'Lys-36' (H3K36Me2), however, the relevance of this result remains unsure in vivo. Specifically binds trimethylated 'Lys-4' of histone H3 (H3K4me3), affecting histone demethylase specificity: has weak activity toward H3K9Me2 in absence of H3K4me3, while it has high activity toward H3K9me2 when binding H3K4me3.[10] [11] [12] [13] [14] [15] [16] [17] [18] [19]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Crystallographic analysis of the catalytic domain of PHD finger protein 8 (PHF8), an N(epsilon)-methyl lysine histone demethylase associated with mental retardation and cleft lip/palate, reveals a double-stranded beta-helix fold with conserved Fe(II) and cosubstrate binding sites typical of the 2-oxoglutarate dependent oxygenases. The PHF8 active site is highly conserved with those of the FBXL10/11demethylases, which are also selective for the di-/mono-methylated lysine states, but differs from that of the JMJD2 demethylases which are selective for tri-/di-methylated states. The results rationalize the lack of activity for the clinically observed F279S PHF8 variant and they will help to identify inhibitors selective for specific N(epsilon)-methyl lysine demethylase subfamilies.
Crystal structure of the PHF8 Jumonji domain, an Nepsilon-methyl lysine demethylase.,Yue WW, Hozjan V, Ge W, Loenarz C, Cooper CD, Schofield CJ, Kavanagh KL, Oppermann U, McDonough MA FEBS Lett. 2010 Feb 19;584(4):825-30. Epub 2010 Jan 12. PMID:20067792[20]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Qiu J, Shi G, Jia Y, Li J, Wu M, Li J, Dong S, Wong J. The X-linked mental retardation gene PHF8 is a histone demethylase involved in neuronal differentiation. Cell Res. 2010 Aug;20(8):908-18. doi: 10.1038/cr.2010.81. Epub 2010 Jun 15. PMID:20548336 doi:10.1038/cr.2010.81
- ↑ Kleine-Kohlbrecher D, Christensen J, Vandamme J, Abarrategui I, Bak M, Tommerup N, Shi X, Gozani O, Rappsilber J, Salcini AE, Helin K. A functional link between the histone demethylase PHF8 and the transcription factor ZNF711 in X-linked mental retardation. Mol Cell. 2010 Apr 23;38(2):165-78. doi: 10.1016/j.molcel.2010.03.002. Epub 2010 , Mar 25. PMID:20346720 doi:10.1016/j.molcel.2010.03.002
- ↑ Fortschegger K, de Graaf P, Outchkourov NS, van Schaik FM, Timmers HT, Shiekhattar R. PHF8 targets histone methylation and RNA polymerase II to activate transcription. Mol Cell Biol. 2010 Jul;30(13):3286-98. doi: 10.1128/MCB.01520-09. Epub 2010 Apr , 26. PMID:20421419 doi:10.1128/MCB.01520-09
- ↑ Feng W, Yonezawa M, Ye J, Jenuwein T, Grummt I. PHF8 activates transcription of rRNA genes through H3K4me3 binding and H3K9me1/2 demethylation. Nat Struct Mol Biol. 2010 Apr;17(4):445-50. doi: 10.1038/nsmb.1778. Epub 2010 Mar, 7. PMID:20208542 doi:10.1038/nsmb.1778
- ↑ Qi HH, Sarkissian M, Hu GQ, Wang Z, Bhattacharjee A, Gordon DB, Gonzales M, Lan F, Ongusaha PP, Huarte M, Yaghi NK, Lim H, Garcia BA, Brizuela L, Zhao K, Roberts TM, Shi Y. Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development. Nature. 2010 Jul 22;466(7305):503-7. doi: 10.1038/nature09261. Epub 2010 Jul 11. PMID:20622853 doi:10.1038/nature09261
- ↑ Liu W, Tanasa B, Tyurina OV, Zhou TY, Gassmann R, Liu WT, Ohgi KA, Benner C, Garcia-Bassets I, Aggarwal AK, Desai A, Dorrestein PC, Glass CK, Rosenfeld MG. PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression. Nature. 2010 Jul 22;466(7305):508-12. doi: 10.1038/nature09272. Epub 2010 Jul 11. PMID:20622854 doi:10.1038/nature09272
- ↑ Yu L, Wang Y, Huang S, Wang J, Deng Z, Zhang Q, Wu W, Zhang X, Liu Z, Gong W, Chen Z. Structural insights into a novel histone demethylase PHF8. Cell Res. 2010 Jan 26. PMID:20101266 doi:cr20108
- ↑ Laumonnier F, Holbert S, Ronce N, Faravelli F, Lenzner S, Schwartz CE, Lespinasse J, Van Esch H, Lacombe D, Goizet C, Phan-Dinh Tuy F, van Bokhoven H, Fryns JP, Chelly J, Ropers HH, Moraine C, Hamel BC, Briault S. Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate. J Med Genet. 2005 Oct;42(10):780-6. PMID:16199551 doi:42/10/780
- ↑ Koivisto AM, Ala-Mello S, Lemmela S, Komu HA, Rautio J, Jarvela I. Screening of mutations in the PHF8 gene and identification of a novel mutation in a Finnish family with XLMR and cleft lip/cleft palate. Clin Genet. 2007 Aug;72(2):145-9. PMID:17661819 doi:10.1111/j.1399-0004.2007.00836.x
- ↑ Zhu Z, Wang Y, Li X, Wang Y, Xu L, Wang X, Sun T, Dong X, Chen L, Mao H, Yu Y, Li J, Chen PA, Chen CD. PHF8 is a histone H3K9me2 demethylase regulating rRNA synthesis. Cell Res. 2010 Jul;20(7):794-801. doi: 10.1038/cr.2010.75. Epub 2010 Jun 8. PMID:20531378 doi:10.1038/cr.2010.75
- ↑ Qiu J, Shi G, Jia Y, Li J, Wu M, Li J, Dong S, Wong J. The X-linked mental retardation gene PHF8 is a histone demethylase involved in neuronal differentiation. Cell Res. 2010 Aug;20(8):908-18. doi: 10.1038/cr.2010.81. Epub 2010 Jun 15. PMID:20548336 doi:10.1038/cr.2010.81
- ↑ Loenarz C, Ge W, Coleman ML, Rose NR, Cooper CD, Klose RJ, Ratcliffe PJ, Schofield CJ. PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an Nepsilon-dimethyl lysine demethylase. Hum Mol Genet. 2010 Jan 15;19(2):217-22. doi: 10.1093/hmg/ddp480. Epub 2009 Oct, 19. PMID:19843542 doi:10.1093/hmg/ddp480
- ↑ Kleine-Kohlbrecher D, Christensen J, Vandamme J, Abarrategui I, Bak M, Tommerup N, Shi X, Gozani O, Rappsilber J, Salcini AE, Helin K. A functional link between the histone demethylase PHF8 and the transcription factor ZNF711 in X-linked mental retardation. Mol Cell. 2010 Apr 23;38(2):165-78. doi: 10.1016/j.molcel.2010.03.002. Epub 2010 , Mar 25. PMID:20346720 doi:10.1016/j.molcel.2010.03.002
- ↑ Fortschegger K, de Graaf P, Outchkourov NS, van Schaik FM, Timmers HT, Shiekhattar R. PHF8 targets histone methylation and RNA polymerase II to activate transcription. Mol Cell Biol. 2010 Jul;30(13):3286-98. doi: 10.1128/MCB.01520-09. Epub 2010 Apr , 26. PMID:20421419 doi:10.1128/MCB.01520-09
- ↑ Feng W, Yonezawa M, Ye J, Jenuwein T, Grummt I. PHF8 activates transcription of rRNA genes through H3K4me3 binding and H3K9me1/2 demethylation. Nat Struct Mol Biol. 2010 Apr;17(4):445-50. doi: 10.1038/nsmb.1778. Epub 2010 Mar, 7. PMID:20208542 doi:10.1038/nsmb.1778
- ↑ Qi HH, Sarkissian M, Hu GQ, Wang Z, Bhattacharjee A, Gordon DB, Gonzales M, Lan F, Ongusaha PP, Huarte M, Yaghi NK, Lim H, Garcia BA, Brizuela L, Zhao K, Roberts TM, Shi Y. Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development. Nature. 2010 Jul 22;466(7305):503-7. doi: 10.1038/nature09261. Epub 2010 Jul 11. PMID:20622853 doi:10.1038/nature09261
- ↑ Liu W, Tanasa B, Tyurina OV, Zhou TY, Gassmann R, Liu WT, Ohgi KA, Benner C, Garcia-Bassets I, Aggarwal AK, Desai A, Dorrestein PC, Glass CK, Rosenfeld MG. PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression. Nature. 2010 Jul 22;466(7305):508-12. doi: 10.1038/nature09272. Epub 2010 Jul 11. PMID:20622854 doi:10.1038/nature09272
- ↑ Yu L, Wang Y, Huang S, Wang J, Deng Z, Zhang Q, Wu W, Zhang X, Liu Z, Gong W, Chen Z. Structural insights into a novel histone demethylase PHF8. Cell Res. 2010 Jan 26. PMID:20101266 doi:cr20108
- ↑ Horton JR, Upadhyay AK, Qi HH, Zhang X, Shi Y, Cheng X. Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylases. Nat Struct Mol Biol. 2010 Jan;17(1):38-43. Epub 2009 Dec 20. PMID:20023638 doi:10.1038/nsmb.1753
- ↑ Yue WW, Hozjan V, Ge W, Loenarz C, Cooper CD, Schofield CJ, Kavanagh KL, Oppermann U, McDonough MA. Crystal structure of the PHF8 Jumonji domain, an Nepsilon-methyl lysine demethylase. FEBS Lett. 2010 Feb 19;584(4):825-30. Epub 2010 Jan 12. PMID:20067792 doi:10.1016/j.febslet.2009.12.055
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