KDM2B

KDM2B
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	4O64
Identifikatori
Aliasi	KDM2B
Vanjski ID-jevi	OMIM: 609078 MGI: 1354737 HomoloGene: 13069 GeneCards: KDM2B
Lokacija gena (čovjek)
Hrom.	Hromosom 12 (čovjek)
Kraj	121,581,023 bp
Lokacija gena (miš)
Hrom.	Hromosom 5 (miš)
Kraj	123,127,886 bp
Ontologija gena
Molekularna funkcija	• vezivanje sa DNK; • rRNA binding; • vezivanje iona cinka; • dioxygenase activity; • vezivanje iona metala; • histone demethylase activity; • GO:0001948, GO:0016582 vezivanje za proteine; • histone H3-methyl-lysine-36 demethylase activity; • vezivanje sa RNK; • oxidoreductase activity; • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding;
Ćelijska komponenta	• nukleoplazma; • Jedarce; • PcG protein complex; • jedro; • hromosom;
Biološki proces	• GO:1904089 negative regulation of neuron apoptotic process; • midbrain-hindbrain boundary morphogenesis; • GO:0009373 regulation of transcription, DNA-templated; • lateral ventricle development; • histone H2A monoubiquitination; • negative regulation of neural precursor cell proliferation; • hindbrain development; • GO:1901227 negative regulation of transcription by RNA polymerase II; • transcription, DNA-templated; • third ventricle development; • positive regulation of cell growth; • embryonic camera-type eye morphogenesis; • histone H3-K36 demethylation; • Spermatogeneza; • forebrain development; • positive regulation of stem cell population maintenance; • initiation of neural tube closure; • midbrain development; • fourth ventricle development; • GO:0031497, GO:0006336, GO:0034724, GO:0001301, GO:0007580, GO:0034652, GO:0010847 chromatin organization;
	Izvori:Amigo / QuickGO
Ortolozi
	84678
	30841
	ENSG00000089094
	ENSMUSG00000029475
	Q8NHM5
	Q6P1G2
	NM_001005366; NM_032590
NM_001003953; NM_001005866; NM_013910; NM_001378863; NM_001378864;
	NM_001378865
	NP_001005366; NP_115979
	NP_001003953; NP_038938; NP_001365792; NP_001365793; NP_001365794
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Ljudski gen KDM2B kodira enzimski protein lizin (K)-specifičma demetilaza 2B.^[5]

Tkivna i subćelijska distribucija

KDM2B je široko i visoko eksprimiran u embrionskim tkivima (posebno u razvoju centralnog nervnog sistema kičmenjaka). Ekspresija KDM2B je također zadržana u većini organa kod odraslih.^[6] Protein je prisutan u nukleoplazmi i obogaćen je u jedarcetu, gdje veže transkribiranu regiju ribosomske RNK (rRNK), kako bi potisnuo transkripciju gena ribosomske RNK koja inhibira rast i proliferaciju ćelija.^[7]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 1.336 aminokiselina, a molekulska težina 152.615 Da.^[8].

10	20	30	40	50
MAGPQMGGSA	EDHPPRKRHA	AEKQKKKTVI	YTKCFEFESA	TQRPIDRQRY
DENEDLSDVE	EIVSVRGFSL	EEKLRSQLYQ	GDFVHAMEGK	DFNYEYVQRE
ALRVPLIFRE	KDGLGIKMPD	PDFTVRDVKL	LVGSRRLVDV	MDVNTQKGTE
MSMSQFVRYY	ETPEAQRDKL	YNVISLEFSH	TKLEHLVKRP	TVVDLVDWVD
NMWPQHLKEK	QTEATNAIAE	MKYPKVKKYC	LMSVKGCFTD	FHIDFGGTSV
WYHVFRGGKI	FWLIPPTLHN	LALYEEWVLS	GKQSDIFLGD	RVERCQRIEL
KQGYTFFIPS	GWIHAVYTPV	DSLVFGGNIL	HSFNVPMQLR	IYEIEDRTRV
QPKFRYPFYY	EMCWYVLERY	VYCVTQRSHL	TQEYQRESML	IDAPRKPSID
GFSSDSWLEM	EEEACDQQPQ	EEEEKDEEGE	GRDRAPKPPT	DGSTSPTSTP
SEDQEALGKK	PKAPALRFLK	RTLSNESEES	VKSTTLAVDY	PKTPTGSPAT
EVSAKWTHLT	EFELKGLKAL	VEKLESLPEN	KKCVPEGIED	PQALLEGVKN
VLKEHADDDP	SLAITGVPVV	TWPKKTPKNR	AVGRPKGKLG	PASAVKLAAN
RTTAGARRRR	TRCRKCEACL	RTECGECHFC	KDMKKFGGPG	RMKQSCIMRQ
CIAPVLPHTA	VCLVCGEAGK	EDTVEEEEGK	FNLMLMECSI	CNEIIHPGCL
KIKESEGVVN	DELPNCWECP	KCNHAGKTGK	QKRGPGFKYA	SNLPGSLLKE
QKMNRDNKEG	QEPAKRRSEC	EEAPRRRSDE	HSKKVPPDGL	LRRKSDDVHL
RKKRKYEKPQ	ELSGRKRASS	LQTSPGSSSH	LSPRPPLGSS	LSPWWRSSLT
YFQQQLKPGK	EDKLFRKKRR	SWKNAEDRMA	LANKPLRRFK	QEPEDELPEA
PPKTRESDHS	RSSSPTAGPS	TEGAEGPEEK	KKVKMRRKRR	LPNKELSREL
SKELNHEIQR	TENSLANENQ	QPIKSEPESE	GEEPKRPPGI	CERPHRFSKG
LNGTPRELRH	QLGPSLRSPP	RVISRPPPSV	SPPKCIQMER	HVIRPPPISP
PPDSLPLDDG	AAHVMHREVW	MAVFSYLSHQ	DLCVCMRVCR	TWNRWCCDKR
LWTRIDLNHC	KSITPLMLSG	IIRRQPVSLD	LSWTNISKKQ	LSWLINRLPG
LRDLVLSGCS	WIAVSALCSS	SCPLLRTLDV	QWVEGLKDAQ	MRDLLSPPTD
NRPGQMDNRS	KLRNIVELRL	AGLDITDASL	RLIIRHMPLL	SKLHLSYCNH
VTDQSINLLT	AVGTTTRDSL	TEINLSDCNK	VTDQCLSFFK	RCGNICHIDL
RYCKQVTKEG	CEQFIAEMSV	SVQFGQVEEK	LLQKLS

Simboli

C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin

Struktura

Protein KDM2B ima nekoliko domena, uključujući JmjC domen, koji ima aktivnost histon-demetilaze demetilirajući trimetilirani Lys-4 i dimetilirani Lys-36 histona H3.^[7]^[9] KDM2B posebno prepoznaje i veže nemetiliranu DNK na CpG-otocima preko svog domena vezanja ZF-CxxC DNK.^[10] KDM2B posljedično regrutira nekanonski polikombni represivni kompleks 1.1 (ncPRC1) na nemetilirane CpG otoke, direktnom interakcijom sa BCOR i PCGF1^[11] što dovodi do mono-ubikvililacije histona H2A na K119 i represije gena.^[12]^[13]^[14]^[15]^[16]

Funkcija

Ovaj gen kodira člana porodice proteina F-kutije, koju karakterizira motiv od približno 40 aminokiselina. Proteini F-kutije čine jednu od četiri podjedinice kompleksa ubikvitinskih proteinskih ligaza zvanog SCF (SKP1-kulin-F-kutija), koji funkcioniraju u fosforilacijski zavisnoj ubikvitinaciji. Proteini F-kutije su podijeljeni u 3 klase: Fbws koji sadrže domene WD-40, Fbls koji sadrže leucin-bogate ponavljanja i Fbxs koji sadrže ili različite module interakcije protein-protein ili bez prepoznatljivih motiva. Protein kodiran ovim genom pripada klasi Fbls. Za ovaj gen pronađeno je više alternativnih prerađenih varijanti transkripta , ali priroda nekih varijanti u cijeloj dužini nije utvrđena.^[5]

Kao dio kompleksa ncPRC1.1, utvrđeno je da se KDM2B brzo i prolazno regrutira na mjesta oštećenja DNK na način ovisan o PARP1 i bezvremeno, kako bi se podsticala mono-ubikvitinacija histona H2A na K119 uz istodobno lokalno smanjenje razine H2A i povećanje H2A.Z. Ovi događaji podstiču transkripcijsku represiju na lezijama DNK, signalizaciju prekida dvostrukih lanaca i popravak homologne rekombinacije. Aktivnost kompleksa ncPRC1.1 na lezijama DNK bila je neophodna za pravilno regrutiranje dva kanonska kompleksa PRC1 (cPRC1.2 i cPRC1.4), definirana njihovim PCGF podjedinicama, MEL18 i BMI1. Stoga aktiviranje kompleksa ncPRC1.1 predstavlja rani i kritični regulatorni korak u popravci homologne rekombinacije.^[17]

Klinićki značaj

Gubitak KDM2B dovodi do ozbiljnih razvojnih nedostataka (defekti rasta u mozgu, uključujući neuspjeh zatvaranja nervne cijevi i kraniofacijalne malformacije, hematopoetski razvoj) što dovodi do smrtnosti embriona^[18]

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000089094 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000029475 - Ensembl, maj 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. doi:10.1371/journal.pone.0136929. PMC 4556705. PMID 26327321.
^ ^a ^b Frescas D, Guardavaccaro D, Bassermann F, Koyama-Nasu R, Pagano M (novembar 2007). "JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes". Nature. 450 (7167): 309–13. doi:10.1038/nature06255. PMID 17994099. S2CID 4325942.
^ "UniProt, Q8NHM5". Pristupljeno 10. 8. 2021.
^ Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, Zhang Y (februar 2006). "Histone demethylation by a family of JmjC domain-containing proteins". Nature. 439 (7078): 811–6. doi:10.1038/nature04433. PMID 16362057. S2CID 4415889.
^ Farcas AM, Blackledge NP, Sudbery I, Long HK, McGouran JF, Rose NR, et al. (decembar 2012). Struhl K (ured.). "KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands". eLife. 1: e00205. doi:10.7554/eLife.00205. PMID 23256043.
^ Wong SJ, Gearhart MD, Taylor AB, Nanyes DR, Ha DJ, Robinson AK, et al. (oktobar 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. (februar 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 (maj 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 (septembar 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 (mart 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 (februar 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 (juli 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 (maj 2015). "FBXL10 protects Polycomb-bound genes from hypermethylation". Nature Genetics. 45 (5): 479–485. doi:10.1038/ng.3272. PMID 25848754.CS1 održavanje: upotreba parametra authors (link)

Dopunska literatura

Fujino T, Hasegawa M, Shibata S, Kishimoto T, Imai S, Takano T (maj 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 (februar 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 (februar 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. doi:10.1073/pnas.0813139106. PMC 2650317. PMID 19202064.
Janzer A, Stamm K, Becker A, Zimmer A, Buettner R, Kirfel J (septembar 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 (novembar 2007). "JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes". Nature. 450 (7167): 309–13. doi:10.1038/nature06255. PMID 17994099. S2CID 4325942.
Koyama-Nasu R, David G, Tanese N (septembar 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 (februar 2006). "Histone demethylation by a family of JmjC domain-containing proteins". Nature. 439 (7078): 811–6. doi:10.1038/nature04433. PMID 16362057. S2CID 4415889.
Ge R, Wang Z, Zeng Q, Xu X, Olumi AF (juli 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.

Vanjski linkovi

Q8NHM5

Ovaj članak uključuje tekst iz Nacionalne medicinske biblioteke Sjedinjenih Država, koji je u javnom vlasništvu.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000089094 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000029475 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-5] "Entrez Gene: Lysine (K)-specific demethylase 2B".

[6] 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. doi:10.1371/journal.pone.0136929. PMC 4556705. PMID 26327321.

[pmid17994099-7] Frescas D, Guardavaccaro D, Bassermann F, Koyama-Nasu R, Pagano M (novembar 2007). "JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes". Nature. 450 (7167): 309–13. doi:10.1038/nature06255. PMID 17994099. S2CID 4325942.

[UniProt-8] "UniProt, Q8NHM5". Pristupljeno 10. 8. 2021.

[9] Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, Zhang Y (februar 2006). "Histone demethylation by a family of JmjC domain-containing proteins". Nature. 439 (7078): 811–6. doi:10.1038/nature04433. PMID 16362057. S2CID 4415889.

[10] Farcas AM, Blackledge NP, Sudbery I, Long HK, McGouran JF, Rose NR, et al. (decembar 2012). Struhl K (ured.). "KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands". eLife. 1: e00205. doi:10.7554/eLife.00205. PMID 23256043.

[11] Wong SJ, Gearhart MD, Taylor AB, Nanyes DR, Ha DJ, Robinson AK, et al. (oktobar 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.

[12] Gao Z, Zhang J, Bonasio R, Strino F, Sawai A, Parisi F, et al. (februar 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.

[13] Sánchez C, Sánchez I, Demmers JA, Rodriguez P, Strouboulis J, Vidal M (maj 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.

[14] Gearhart MD, Corcoran CM, Wamstad JA, Bardwell VJ (septembar 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.

[15] Andricovich J, Kai Y, Peng W, Foudi A, Tzatsos A (mart 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.

[16] Tamburri S, Lavarone E, Fernández-Pérez D, Conway E, Zanotti M, Manganaro D, Pasini D (februar 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.

[17] Rona G, Roberti D, Yin Y, Pagan JK, Homer H, Sassani E, Zeke A, Busino L, Rothenberg E, Pagano M (juli 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.

[18] Boulard, M, Edwards, JR, Bestor, TH (maj 2015). "FBXL10 protects Polycomb-bound genes from hypermethylation". Nature Genetics. 45 (5): 479–485. doi:10.1038/ng.3272. PMID 25848754.CS1 održavanje: upotreba parametra authors (link)

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