KDM2B
The human KDM2B gene encodes the protein lysine (K)-specific demethylase 2B.[5]
Tissue and subcellular distribution
[edit]KDM2B is broadly and highly expressed in embryonic tissues (especially in the developing central nervous system of vertebrates). Expression of KDM2B is also retained in most organs in adults.[6] The protein is present in the nucleoplasm and is enriched in the nucleolus where it binds the transcribed region of ribosomal RNA to represses the transcription of ribosomal RNA genes which inhibits cell growth and proliferation.[7]
Structure
[edit]KDM2B protein has several domains including a JmjC domain that has a histone demethylase activity demethylating trimethylated Lys-4 and dimethylated Lys-36 of histone H3.[8][7] KDM2B specifically recognizes and bind non-methylated DNA in CpG islands through its ZF-CxxC DNA binding domain.[9] KDM2B consequently recruits the non-canonical polycomb repressive complex 1.1 (ncPRC1) to unmethylated CpG islands via a direct interaction with BCOR and PCGF1[10] leading to the mono-ubiquitylation of histone H2A on K119 and gene repression.[11][12][13][14][15]
Function
[edit]This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class. Multiple alternatively spliced transcript variants have been found for this gene, but the full-length nature of some variants has not been determined.[5]
As part of the ncPRC1.1 complex, KDM2B was found to be rapidly and transiently recruited to sites of DNA damage in a PARP1- and TIMELESS-dependent manner to promote mono-ubiquitylation of histone H2A on K119 with concomitant local decrease of H2A levels and an increase of H2A.Z. These events promote transcriptional repression at DNA lesions, double strand break signaling, and homologous recombination repair. The activity of the ncPRC1.1 complex at DNA lesions was necessary for the proper recruitment of the two canonical PRC1 complexes (cPRC1.2 and cPRC1.4), defined by their PCGF subunits, MEL18 and BMI1 respectively. Therefore, recruitment of the ncPRC1.1 complex represents an early and critical regulatory step in homologous recombination repair.[16]
Clinical significance
[edit]Loss of KDM2B leads to severe developmental defects (growth defects in the brain, including failure of neural tube closure and craniofacial malformations, hematopoietic development) leading to embryonic lethality[17]
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000089094 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029475 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b "Entrez Gene: Lysine (K)-specific demethylase 2B".
- ^ Saritas-Yildirim B, Pliner HA, Ochoa A, Silva EM (2015). "Genome-Wide Identification and Expression of Xenopus F-Box Family of Proteins". PLOS ONE. 10 (9): e0136929. Bibcode:2015PLoSO..1036929S. doi:10.1371/journal.pone.0136929. PMC 4556705. PMID 26327321.
- ^ a b Frescas D, Guardavaccaro D, Bassermann F, Koyama-Nasu R, Pagano M (November 2007). "JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes". Nature. 450 (7167): 309–13. Bibcode:2007Natur.450..309F. doi:10.1038/nature06255. PMID 17994099. S2CID 4325942.
- ^ Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, Zhang Y (February 2006). "Histone demethylation by a family of JmjC domain-containing proteins". Nature. 439 (7078): 811–6. Bibcode:2006Natur.439..811T. doi:10.1038/nature04433. PMID 16362057. S2CID 4415889.
- ^ Farcas AM, Blackledge NP, Sudbery I, Long HK, McGouran JF, Rose NR, et al. (December 2012). Struhl K (ed.). "KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands". eLife. 1: e00205. doi:10.7554/eLife.00205. PMC 3524939. PMID 23256043.
- ^ Wong SJ, Gearhart MD, Taylor AB, Nanyes DR, Ha DJ, Robinson AK, et al. (October 2016). "KDM2B Recruitment of the Polycomb Group Complex, PRC1.1, Requires Cooperation between PCGF1 and BCORL1". Structure. 24 (10): 1795–1801. doi:10.1016/j.str.2016.07.011. PMC 5088048. PMID 27568929.
- ^ Gao Z, Zhang J, Bonasio R, Strino F, Sawai A, Parisi F, et al. (February 2012). "PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes". Molecular Cell. 45 (3): 344–56. doi:10.1016/j.molcel.2012.01.002. PMC 3293217. PMID 22325352.
- ^ Sánchez C, Sánchez I, Demmers JA, Rodriguez P, Strouboulis J, Vidal M (May 2007). "Proteomics analysis of Ring1B/Rnf2 interactors identifies a novel complex with the Fbxl10/Jhdm1B histone demethylase and the Bcl6 interacting corepressor". Molecular & Cellular Proteomics. 6 (5): 820–34. doi:10.1074/mcp.M600275-MCP200. PMID 17296600.
- ^ Gearhart MD, Corcoran CM, Wamstad JA, Bardwell VJ (September 2006). "Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets". Molecular and Cellular Biology. 26 (18): 6880–9. doi:10.1128/MCB.00630-06. PMC 1592854. PMID 16943429.
- ^ Andricovich J, Kai Y, Peng W, Foudi A, Tzatsos A (March 2016). "Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis". The Journal of Clinical Investigation. 126 (3): 905–20. doi:10.1172/JCI84014. PMC 4767361. PMID 26808549.
- ^ Tamburri S, Lavarone E, Fernández-Pérez D, Conway E, Zanotti M, Manganaro D, Pasini D (February 2020). "Histone H2AK119 Mono-Ubiquitination Is Essential for Polycomb-Mediated Transcriptional Repression". Molecular Cell. 77 (4): 840–856.e5. doi:10.1016/j.molcel.2019.11.021. PMC 7033561. PMID 31883952.
- ^ Rona G, Roberti D, Yin Y, Pagan JK, Homer H, Sassani E, Zeke A, Busino L, Rothenberg E, Pagano M (July 2018). "PARP1-dependent recruitment of the FBXL10-RNF68-RNF2 ubiquitin ligase to sites of DNA damage controls H2A.Z loading". eLife. 7. doi:10.7554/eLife.38771. PMC 6037479. PMID 29985131.
- ^ Boulard, M; Edwards, JR; Bestor, TH (May 2015). "FBXL10 protects Polycomb-bound genes from hypermethylation". Nature Genetics. 45 (5): 479–485. doi:10.1038/ng.3272. PMID 25848754. S2CID 205349859.
Further reading
[edit]- Fujino T, Hasegawa M, Shibata S, Kishimoto T, Imai S, Takano T (May 2000). "PCCX1, a novel DNA-binding protein with PHD finger and CXXC domain, is regulated by proteolysis". Biochemical and Biophysical Research Communications. 271 (2): 305–10. doi:10.1006/bbrc.2000.2614. PMID 10799292.
- Tzatsos A, Paskaleva P, Ferrari F, Deshpande V, Stoykova S, Contino G, Wong KK, Lan F, Trojer P, Park PJ, Bardeesy N (February 2013). "KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs". The Journal of Clinical Investigation. 123 (2): 727–39. doi:10.1172/JCI64535. PMC 3561797. PMID 23321669.
- Tzatsos A, Pfau R, Kampranis SC, Tsichlis PN (February 2009). "Ndy1/KDM2B immortalizes mouse embryonic fibroblasts by repressing the Ink4a/Arf locus". Proceedings of the National Academy of Sciences of the United States of America. 106 (8): 2641–6. Bibcode:2009PNAS..106.2641T. doi:10.1073/pnas.0813139106. PMC 2650317. PMID 19202064.
- Janzer A, Stamm K, Becker A, Zimmer A, Buettner R, Kirfel J (September 2012). "The H3K4me3 histone demethylase Fbxl10 is a regulator of chemokine expression, cellular morphology, and the metabolome of fibroblasts". The Journal of Biological Chemistry. 287 (37): 30984–92. doi:10.1074/jbc.M112.341040. PMC 3438931. PMID 22825849.
- Frescas D, Guardavaccaro D, Bassermann F, Koyama-Nasu R, Pagano M (November 2007). "JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes". Nature. 450 (7167): 309–13. Bibcode:2007Natur.450..309F. doi:10.1038/nature06255. PMID 17994099. S2CID 4325942.
- Koyama-Nasu R, David G, Tanese N (September 2007). "The F-box protein Fbl10 is a novel transcriptional repressor of c-Jun". Nature Cell Biology. 9 (9): 1074–80. doi:10.1038/ncb1628. PMID 17704768. S2CID 30551299.
- Szafranski K, Schindler S, Taudien S, Hiller M, Huse K, Jahn N, Schreiber S, Backofen R, Platzer M (2007). "Violating the splicing rules: TG dinucleotides function as alternative 3' splice sites in U2-dependent introns". Genome Biology. 8 (8): R154. doi:10.1186/gb-2007-8-8-r154. PMC 2374985. PMID 17672918.
- Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, Zhang Y (February 2006). "Histone demethylation by a family of JmjC domain-containing proteins". Nature. 439 (7078): 811–6. Bibcode:2006Natur.439..811T. doi:10.1038/nature04433. PMID 16362057. S2CID 4415889.
- Ge R, Wang Z, Zeng Q, Xu X, Olumi AF (July 2011). "F-box protein 10, an NF-κB-dependent anti-apoptotic protein, regulates TRAIL-induced apoptosis through modulating c-Fos/c-FLIP pathway". Cell Death and Differentiation. 18 (7): 1184–95. doi:10.1038/cdd.2010.185. PMC 3131965. PMID 21252908.
External links
[edit]- Overview of all the structural information available in the PDB for UniProt: Q8NHM5 (Lysine-specific demethylase 2B) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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