Transkripcijski regulator ATRX znan i kao ATP-ovisna helikaza ATRX, X-vezana helikaza II, ili X-vezani jedarni protein (XNP) jest protein koji je kod ljudi kodiran genom ATRX sa hromosoma X.[5][6][7]
Kratke činjenice Dostupne strukture, PDB ...
Transkripcijski regulator ATRX |
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Identifikatori |
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Aliasi | ATRX |
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Vanjski ID-jevi | OMIM: 300032 MGI: 103067 HomoloGene: 416 GeneCards: ATRX |
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Ontologija gena |
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Molekularna funkcija | • vezivanje sa DNK • nucleotide binding • chromo shadow domain binding • GO:0008026 helicase activity • GO:0031493 histone binding • vezivanje iona metala • DNA translocase activity • methylated histone binding • GO:0004003 DNA helicase activity • GO:0001948, GO:0016582 vezivanje za proteine • hydrolase activity • ATP binding • chromatin binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific
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Ćelijska komponenta | • PML body • SWI/SNF superfamily-type complex • pericentric heterochromatin • hromosom • GO:0035328 heterochromatin • nuclear chromosome • Telomera • jedro • nukleoplazma • nuclear body
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Biološki proces | • chromatin remodeling • nucleosome assembly • DNA recombination • post-embryonic forelimb morphogenesis • GO:0009373 regulation of transcription, DNA-templated • multicellular organism growth • DNA damage response, signal transduction by p53 class mediator • positive regulation of nuclear cell cycle DNA replication • Sertoli cell development • transcription, DNA-templated • protein localization to chromosome, telomeric region • cellular response to DNA damage stimulus • positive regulation of telomeric RNA transcription from RNA pol II promoter • positive regulation of telomere maintenance • Metilacija DNK • negative regulation of telomeric RNA transcription from RNA pol II promoter • seminiferous tubule development • Spermatogeneza • replication fork processing • negative regulation of maintenance of mitotic sister chromatid cohesion, telomeric • forebrain development • GO:0100026 Popravka DNK • cellular response to hydroxyurea • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II • DNA duplex unwinding • regulation of histone H3-K9 trimethylation • GO:0043147 meiotic spindle organization • GO:0051178 chromosome organization involved in meiotic cell cycle • GO:0031497, GO:0006336, GO:0034724, GO:0001301, GO:0007580, GO:0034652, GO:0010847 chromatin organization
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Izvori:Amigo / QuickGO |
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Ortolozi |
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Vrste | Čovjek | Miš |
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Entrez | | |
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Ensembl | | |
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UniProt | | |
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RefSeq (mRNK) | | |
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RefSeq (bjelančevina) | | |
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Lokacija (UCSC) | Chr X: 77.5 – 77.79 Mb | Chr X: 104.84 – 104.97 Mb |
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PubMed pretraga | [3] | [4] |
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Wikipodaci |
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Zatvori
Dužina polipeptidnog lanca je 2.492 aminokiseline, a molekulska težina 282.586 Da.[7]
10 | | 20 | | 30 | | 40 | | 50 |
MTAEPMSESK | | LNTLVQKLHD | | FLAHSSEESE | | ETSSPPRLAM | | NQNTDKISGS |
GSNSDMMENS | | KEEGTSSSEK | | SKSSGSSRSK | | RKPSIVTKYV | | ESDDEKPLDD |
ETVNEDASNE | | NSENDITMQS | | LPKGTVIVQP | | EPVLNEDKDD | | FKGPEFRSRS |
KMKTENLKKR | | GEDGLHGIVS | | CTACGQQVNH | | FQKDSIYRHP | | SLQVLICKNC |
FKYYMSDDIS | | RDSDGMDEQC | | RWCAEGGNLI | | CCDFCHNAFC | | KKCILRNLGR |
KELSTIMDEN | | NQWYCYICHP | | EPLLDLVTAC | | NSVFENLEQL | | LQQNKKKIKV |
DSEKSNKVYE | | HTSRFSPKKT | | SSNCNGEEKK | | LDDSCSGSVT | | YSYSALIVPK |
EMIKKAKKLI | | ETTANMNSSY | | VKFLKQATDN | | SEISSATKLR | | QLKAFKSVLA |
DIKKAHLALE | | EDLNSEFRAM | | DAVNKEKNTK | | EHKVIDAKFE | | TKARKGEKPC |
ALEKKDISKS | | EAKLSRKQVD | | SEHMHQNVPT | | EEQRTNKSTG | | GEHKKSDRKE |
EPQYEPANTS | | EDLDMDIVSV | | PSSVPEDIFE | | NLETAMEVQS | | SVDHQGDGSS |
GTEQEVESSS | | VKLNISSKDN | | RGGIKSKTTA | | KVTKELYVKL | | TPVSLSNSPI |
KGADCQEVPQ | | DKDGYKSCGL | | NPKLEKCGLG | | QENSDNEHLV | | ENEVSLLLEE |
SDLRRSPRVK | | TTPLRRPTET | | NPVTSNSDEE | | CNETVKEKQK | | LSVPVRKKDK |
RNSSDSAIDN | | PKPNKLPKSK | | QSETVDQNSD | | SDEMLAILKE | | VSRMSHSSSS |
DTDINEIHTN | | HKTLYDLKTQ | | AGKDDKGKRK | | RKSSTSGSDF | | DTKKGKSAKS |
SIISKKKRQT | | QSESSNYDSE | | LEKEIKSMSK | | IGAARTTKKR | | IPNTKDFDSS |
EDEKHSKKGM | | DNQGHKNLKT | | SQEGSSDDAE | | RKQERETFSS | | AEGTVDKDTT |
IMELRDRLPK | | KQQASASTDG | | VDKLSGKEQS | | FTSLEVRKVA | | ETKEKSKHLK |
TKTCKKVQDG | | LSDIAEKFLK | | KDQSDETSED | | DKKQSKKGTE | | EKKKPSDFKK |
KVIKMEQQYE | | SSSDGTEKLP | | EREEICHFPK | | GIKQIKNGTT | | DGEKKSKKIR |
DKTSKKKDEL | | SDYAEKSTGK | | GDSCDSSEDK | | KSKNGAYGRE | | KKRCKLLGKS |
SRKRQDCSSS | | DTEKYSMKED | | GCNSSDKRLK | | RIELRERRNL | | SSKRNTKEIQ |
SGSSSSDAEE | | SSEDNKKKKQ | | RTSSKKKAVI | | VKEKKRNSLR | | TSTKRKQADI |
TSSSSSDIED | | DDQNSIGEGS | | SDEQKIKPVT | | ENLVLSSHTG | | FCQSSGDEAL |
SKSVPVTVDD | | DDDDNDPENR | | IAKKMLLEEI | | KANLSSDEDG | | SSDDEPEEGK |
KRTGKQNEEN | | PGDEEAKNQV | | NSESDSDSEE | | SKKPRYRHRL | | LRHKLTVSDG |
ESGEEKKTKP | | KEHKEVKGRN | | RRKVSSEDSE | | DSDFQESGVS | | EEVSESEDEQ |
RPRTRSAKKA | | ELEENQRSYK | | QKKKRRRIKV | | QEDSSSENKS | | NSEEEEEEKE |
EEEEEEEEEE | | EEEEDENDDS | | KSPGKGRKKI | | RKILKDDKLR | | TETQNALKEE |
EERRKRIAER | | EREREKLREV | | IEIEDASPTK | | CPITTKLVLD | | EDEETKEPLV |
QVHRNMVIKL | | KPHQVDGVQF | | MWDCCCESVK | | KTKKSPGSGC | | ILAHCMGLGK |
TLQVVSFLHT | | VLLCDKLDFS | | TALVVCPLNT | | ALNWMNEFEK | | WQEGLKDDEK |
LEVSELATVK | | RPQERSYMLQ | | RWQEDGGVMI | | IGYEMYRNLA | | QGRNVKSRKL |
KEIFNKALVD | | PGPDFVVCDE | | GHILKNEASA | | VSKAMNSIRS | | RRRIILTGTP |
LQNNLIEYHC | | MVNFIKENLL | | GSIKEFRNRF | | INPIQNGQCA | | DSTMVDVRVM |
KKRAHILYEM | | LAGCVQRKDY | | TALTKFLPPK | | HEYVLAVRMT | | SIQCKLYQYY |
LDHLTGVGNN | | SEGGRGKAGA | | KLFQDFQMLS | | RIWTHPWCLQ | | LDYISKENKG |
YFDEDSMDEF | | IASDSDETSM | | SLSSDDYTKK | | KKKGKKGKKD | | SSSSGSGSDN |
DVEVIKVWNS | | RSRGGGEGNV | | DETGNNPSVS | | LKLEESKATS | | SSNPSSPAPD |
WYKDFVTDAD | | AEVLEHSGKM | | VLLFEILRMA | | EEIGDKVLVF | | SQSLISLDLI |
EDFLELASRE | | KTEDKDKPLI | | YKGEGKWLRN | | IDYYRLDGST | | TAQSRKKWAE |
EFNDETNVRG | | RLFIISTKAG | | SLGINLVAAN | | RVIIFDASWN | | PSYDIQSIFR |
VYRFGQTKPV | | YVYRFLAQGT | | MEDKIYDRQV | | TKQSLSFRVV | | DQQQVERHFT |
MNELTELYTF | | EPDLLDDPNS | | EKKKKRDTPM | | LPKDTILAEL | | LQIHKEHIVG |
YHEHDSLLDH | | KEEEELTEEE | | RKAAWAEYEA | | EKKGLTMRFN | | IPTGTNLPPV |
SFNSQTPYIP | | FNLGALSAMS | | NQQLEDLINQ | | GREKVVEATN | | SVTAVRIQPL |
EDIISAVWKE | | NMNLSEAQVQ | | ALALSRQASQ | | ELDVKRREAI | | YNDVLTKQQM |
LISCVQRILM | | NRRLQQQYNQ | | QQQQQMTYQQ | | ATLGHLMMPK | | PPNLIMNPSN |
YQQIDMRGMY | | QPVAGGMQPP | | PLQRAPPPMR | | SKNPGPSQGK | | SM |
Transkripcijski regulator ATRX sadrži domen ATPaza/helikaza i stoga pripada SWI/SNF porodici proteina hromatinskog remodeliranja. ATRX je neophodan za taloženje histonske varijante H3.3 na telomerama i drugih genomskih ponavljanja.[8] Ove interakcije su važne za održavanje utišavanja na ovim lokusima.[9][10][11]
Osim toga, ATRX prolazi kroz fosforilacije ovisno o ćelijskom ciklusu, koje reguliraju njegovu jedarnu matricu i asocijaciju hromatina, sugerirajući njegovu uključenost u regulaciju gena u interfazi i hromosomsku segregaciju u mitozi.[7]
Naslijeđene mutacije
Naslijeđene mutacije gena ATRX povezane su sa X-vezanim sindromom mentalne retardacije (XLMR) sindromom koji je najčešće praćen alfa-talasemijjskim sindromom mentalne retardacije (sindrom ATR-X). Pokazalo se da ove mutacije uzrokuju različite promjene u obrascu metilacije DNK, što može potvrditi vezu između remodeliranja hromatina, metilacije DNK i ekspresije gena u razvojnim procesima. Zabilježeno je više alternativno prertađemih varijanti transkripta koje kodiraju različite izoforme. Žene nositeljice mogu pokazati iskrivljenu inaktivacija X hromosoma.[7]
ATRX formira kompleks sa DAXX koji je šaperon histona H3.3.[17]
Također se pokazalo da ATRX ima interakcije sa EZH2.[18]
- Sindrom alfa-talasemijske mentalne retardacije
Stayton CL, Dabovic B, Gulisano M, Gecz J, Broccoli V, Giovanazzi S, et al. (novembar 1994). "Cloning and characterization of a new human Xq13 gene, encoding a putative helicase". Human Molecular Genetics. 3 (11): 1957–64. doi:10.1093/hmg/3.11.1957. PMID 7874112. Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, et al. (januar 2012). "Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma". Nature. 482 (7384): 226–31. doi:10.1038/nature10833. PMID 22286061. S2CID 4312169.
- Mulley JC, Kerr B, Stevenson R, Lubs H (1992). "Nomenclature guidelines for X-linked mental retardation". American Journal of Medical Genetics. 43 (1–2): 383–91. doi:10.1002/ajmg.1320430159. PMID 1605216.
- Tang P, Park DJ, Marshall Graves JA, Harley VR (septembar 2004). "ATRX and sex differentiation". Trends in Endocrinology and Metabolism. 15 (7): 339–44. doi:10.1016/j.tem.2004.07.006. PMID 15350606. S2CID 22192941.
- Forget BG (mart 2006). "De novo and acquired forms of alpha thalassemia". Current Hematology Reports. 5 (1): 11–4. PMID 16537041.
- Adès LC, Kerr B, Turner G, Wise G (septembar 1991). "Smith-Fineman-Myers syndrome in two brothers". American Journal of Medical Genetics. 40 (4): 467–70. doi:10.1002/ajmg.1320400419. PMID 1684092.
- Sutherland GR, Gedeon AK, Haan EA, Woodroffe P, Mulley JC (1988). "Linkage studies with the gene for an X-linked syndrome of mental retardation, microcephaly and spastic diplegia (MRX2)". American Journal of Medical Genetics. 30 (1–2): 493–508. doi:10.1002/ajmg.1320300152. PMID 3177467. CS1 održavanje: nepreporučeni parametar (link)
- Shapiro MB, Senapathy P (septembar 1987). "RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression". Nucleic Acids Research. 15 (17): 7155–74. doi:10.1093/nar/15.17.7155. PMC 306199. PMID 3658675.
- Gibbons RJ, Picketts DJ, Villard L, Higgs DR (mart 1995). "Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome)". Cell. 80 (6): 837–45. doi:10.1016/0092-8674(95)90287-2. PMID 7697714.
- Wang LH, Collins A, Lawrence S, Keats BJ, Morton NE (august 1994). "Integration of gene maps: chromosome X". Genomics. 22 (3): 590–604. doi:10.1006/geno.1994.1432. PMID 8001970.
- Gecz J, Pollard H, Consalez G, Villard L, Stayton C, Millasseau P, Khrestchatisky M, Fontes M (januar 1994). "Cloning and expression of the murine homologue of a putative human X-linked nuclear protein gene closely linked to PGK1 in Xq13.3". Human Molecular Genetics. 3 (1): 39–44. doi:10.1093/hmg/3.1.39. PMID 8162050.
- Villard L, Gecz J, Mattéi JF, Fontés M, Saugier-Veber P, Munnich A, Lyonnet S (april 1996). "XNP mutation in a large family with Juberg-Marsidi syndrome". Nature Genetics. 12 (4): 359–60. doi:10.1038/ng0496-359. PMID 8630485. S2CID 33759894.
- Bonaldo MF, Lennon G, Soares MB (septembar 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
- Picketts DJ, Higgs DR, Bachoo S, Blake DJ, Quarrell OW, Gibbons RJ (decembar 1996). "ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome". Human Molecular Genetics. 5 (12): 1899–907. doi:10.1093/hmg/5.12.1899. PMID 8968741.
- Villard L, Lacombe D, Fontés M (1997). "A point mutation in the XNP gene, associated with an ATR-X phenotype without alpha-thalassemia". European Journal of Human Genetics. 4 (6): 316–20. doi:10.1159/000472225. PMID 9043863. S2CID 43618843.
- Villard L, Lossi AM, Cardoso C, Proud V, Chiaroni P, Colleaux L, Schwartz C, Fontés M (juli 1997). "Determination of the genomic structure of the XNP/ATRX gene encoding a potential zinc finger helicase". Genomics. 43 (2): 149–55. doi:10.1006/geno.1997.4793. PMID 9244431.
- Golub EI, Kovalenko OV, Gupta RC, Ward DC, Radding CM (oktobar 1997). "Interaction of human recombination proteins Rad51 and Rad54". Nucleic Acids Research. 25 (20): 4106–10. doi:10.1093/nar/25.20.4106. PMC 147015. PMID 9321665.
- Gibbons RJ, Bachoo S, Picketts DJ, Aftimos S, Asenbauer B, Bergoffen J, Berry SA, Dahl N, Fryer A, Keppler K, Kurosawa K, Levin ML, Masuno M, Neri G, Pierpont ME, Slaney SF, Higgs DR (oktobar 1997). "Mutations in transcriptional regulator ATRX establish the functional significance of a PHD-like domain". Nature Genetics. 17 (2): 146–8. doi:10.1038/ng1097-146. PMID 9326931. S2CID 12470300.
- Cardoso C, Timsit S, Villard L, Khrestchatisky M, Fontès M, Colleaux L (april 1998). "Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein". Human Molecular Genetics. 7 (4): 679–84. doi:10.1093/hmg/7.4.679. PMID 9499421.
- Bérubé NG, Mangelsdorf M, Jagla M, Vanderluit J, Garrick D, Gibbons RJ, Higgs DR, Slack RS, Picketts DJ (februar 2005). "The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis". The Journal of Clinical Investigation. 115 (2): 258–67. doi:10.1172/JCI22329. PMC 544602. PMID 15668733.