KDM2B explained

The human KDM2B gene encodes the protein lysine (K)-specific demethylase 2B.^[1]

Tissue and subcellular distribution

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.^[2] 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.

Structure

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.^{[3] [4]} KDM2B specifically recognizes and bind non-methylated DNA in CpG islands through its ZF-CxxC DNA binding domain.^[5] KDM2B consequently recruits the non-canonical polycomb repressive complex 1.1 (ncPRC1) to unmethylated CpG islands via a direct interaction with BCOR and PCGF1^[6] leading to the mono-ubiquitylation of histone H2A on K119 and gene repression.^{[7] [8] [9] [10] [11]}

Function

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.^[1]

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.^[12]

Clinical significance

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^[13]

Further reading

• Fujino T, Hasegawa M, Shibata S, Kishimoto T, Imai S, Takano T . 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 . May 2000 . 10799292 . 10.1006/bbrc.2000.2614 .
• Tzatsos A, Paskaleva P, Ferrari F, Deshpande V, Stoykova S, Contino G, Wong KK, Lan F, Trojer P, Park PJ, Bardeesy N . KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs . The Journal of Clinical Investigation . 123 . 2 . 727–39 . February 2013 . 23321669 . 3561797 . 10.1172/JCI64535 .
• Tzatsos A, Pfau R, Kampranis SC, Tsichlis PN . 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 . February 2009 . 19202064 . 2650317 . 10.1073/pnas.0813139106 . 2009PNAS..106.2641T . free .
• Janzer A, Stamm K, Becker A, Zimmer A, Buettner R, Kirfel J . 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 . September 2012 . 22825849 . 3438931 . 10.1074/jbc.M112.341040 . free .
• Frescas D, Guardavaccaro D, Bassermann F, Koyama-Nasu R, Pagano M . JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes . Nature . 450 . 7167 . 309–13 . November 2007 . 17994099 . 10.1038/nature06255 . 2007Natur.450..309F . 4325942 .
• Koyama-Nasu R, David G, Tanese N . The F-box protein Fbl10 is a novel transcriptional repressor of c-Jun . Nature Cell Biology . 9 . 9 . 1074–80 . September 2007 . 17704768 . 10.1038/ncb1628 . 30551299 .
• Szafranski K, Schindler S, Taudien S, Hiller M, Huse K, Jahn N, Schreiber S, Backofen R, Platzer M . Violating the splicing rules: TG dinucleotides function as alternative 3' splice sites in U2-dependent introns . Genome Biology . 8 . 8 . R154 . 2007 . 17672918 . 2374985 . 10.1186/gb-2007-8-8-r154 . free .
• Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, Zhang Y . Histone demethylation by a family of JmjC domain-containing proteins . Nature . 439 . 7078 . 811–6 . February 2006 . 16362057 . 10.1038/nature04433 . 2006Natur.439..811T . 4415889 .
• Ge R, Wang Z, Zeng Q, Xu X, Olumi AF . 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 . July 2011 . 21252908 . 3131965 . 10.1038/cdd.2010.185 .

Notes and References

1. Web site: Entrez Gene: Lysine (K)-specific demethylase 2B .
2. Saritas-Yildirim B, Pliner HA, Ochoa A, Silva EM . Genome-Wide Identification and Expression of Xenopus F-Box Family of Proteins . PLOS ONE . 10 . 9 . e0136929 . 2015 . 26327321 . 4556705 . 10.1371/journal.pone.0136929 . 2015PLoSO..1036929S . free .
3. Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, Zhang Y . Histone demethylation by a family of JmjC domain-containing proteins . Nature . 439 . 7078 . 811–6 . February 2006 . 16362057 . 10.1038/nature04433 . 2006Natur.439..811T . 4415889 .
4. Frescas D, Guardavaccaro D, Bassermann F, Koyama-Nasu R, Pagano M . JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes . Nature . 450 . 7167 . 309–13 . November 2007 . 17994099 . 10.1038/nature06255 . 2007Natur.450..309F . 4325942 .
5. Farcas AM, Blackledge NP, Sudbery I, Long HK, McGouran JF, Rose NR, Lee S, Sims D, Cerase A, Sheahan TW, Koseki H, Brockdorff N, Ponting CP, Kessler BM, Klose RJ . 6 . KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands . eLife . 1 . e00205 . December 2012 . 23256043 . 10.7554/eLife.00205 . Struhl K . 3524939 . free .
6. Wong SJ, Gearhart MD, Taylor AB, Nanyes DR, Ha DJ, Robinson AK, Artigas JA, Lee OJ, Demeler B, Hart PJ, Bardwell VJ, Kim CA . 6 . KDM2B Recruitment of the Polycomb Group Complex, PRC1.1, Requires Cooperation between PCGF1 and BCORL1 . Structure . 24 . 10 . 1795–1801 . October 2016 . 27568929 . 5088048 . 10.1016/j.str.2016.07.011 .
7. Gao Z, Zhang J, Bonasio R, Strino F, Sawai A, Parisi F, Kluger Y, Reinberg D . 6 . PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes . Molecular Cell . 45 . 3 . 344–56 . February 2012 . 22325352 . 3293217 . 10.1016/j.molcel.2012.01.002 .
8. Sánchez C, Sánchez I, Demmers JA, Rodriguez P, Strouboulis J, Vidal M . 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 . May 2007 . 17296600 . 10.1074/mcp.M600275-MCP200 . free .
9. 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 . Molecular and Cellular Biology . 26 . 18 . 6880–9 . September 2006 . 16943429 . 1592854 . 10.1128/MCB.00630-06 .
10. Andricovich J, Kai Y, Peng W, Foudi A, Tzatsos A . Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis . The Journal of Clinical Investigation . 126 . 3 . 905–20 . March 2016 . 26808549 . 4767361 . 10.1172/JCI84014 .
11. Tamburri S, Lavarone E, Fernández-Pérez D, Conway E, Zanotti M, Manganaro D, Pasini D . Histone H2AK119 Mono-Ubiquitination Is Essential for Polycomb-Mediated Transcriptional Repression . Molecular Cell . 77 . 4 . 840–856.e5 . February 2020 . 31883952 . 7033561 . 10.1016/j.molcel.2019.11.021 .
12. Rona G, Roberti D, Yin Y, Pagan JK, Homer H, Sassani E, Zeke A, Busino L, Rothenberg E, Pagano M . PARP1-dependent recruitment of the FBXL10-RNF68-RNF2 ubiquitin ligase to sites of DNA damage controls H2A.Z loading . eLife . 7 . July 2018 . 29985131 . 6037479 . 10.7554/eLife.38771 . free .
13. Boulard, M . Edwards, JR . Bestor, TH . FBXL10 protects Polycomb-bound genes from hypermethylation . Nature Genetics. 45 . 5 . 479–485 . May 2015 . 25848754 . 10.1038/ng.3272 . 205349859 .