XPC

XPC
Dostupne strukture PDB Pretraga ortologa: PDBe RCSB Spisak PDB ID kodova 2A4J, 2GGM, 2OBH, 2RVB
Identifikatori
Aliasi	XPC
Vanjski ID-jevi	OMIM: 613208 MGI: 103557 HomoloGene: 3401 GeneCards: XPC
Lokacija gena (miš) Hrom. Hromosom 6 (miš)[1] Bend 6|6 D1 Početak 91,466,287 bp[1] Kraj 91,492,870 bp[1]
Obrazac RNK ekspresije Više referentnih podataka o ekspresiji
Ontologija gena Molekularna funkcija • vezivanje sa DNK • heteroduplex DNA loop binding • bubble DNA binding • single-stranded DNA binding • oštećeno vezivanje sa DNK • GO:0001948, GO:0016582 vezivanje za proteine • GO:0032403 protein-containing complex binding Ćelijska komponenta • citoplazma • ćelijska membrana • nukleoplazma • XPC complex • Jedarce • nucleotide-excision repair factor 2 complex • jedro • mitohondrija • intracellular membrane-bounded organelle • nucleotide-excision repair complex Biološki proces • Popravak ekscizijom nukleotida • regulation of mitotic cell cycle phase transition • nucleotide-excision repair, DNA damage recognition • mitotic intra-S DNA damage checkpoint signaling • cellular response to DNA damage stimulus • global genome nucleotide-excision repair • response to auditory stimulus • Popravak neusklađenosti DNK • response to UV-B • UV-damage excision repair • GO:0100026 Popravka DNK • nucleotide-excision repair, preincision complex assembly • nucleotide-excision repair, DNA duplex unwinding Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	7508	22591
Ensembl	ENSG00000154767	ENSMUSG00000030094
UniProt	Q01831	P51612
RefSeq (mRNK)	NM_001145769 NM_004628	NM_009531
RefSeq (bjelančevina)	NP_004619 NP_001341655 NP_001341656 NP_001341658 NP_001341659	NP_033557
Lokacija (UCSC)	n/a	Chr 6: 91.47 – 91.49 Mb
PubMed pretraga	[2]	[3]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

Xeroderma pigmentosum, komplementacijska grupa C, znana i kao XPC, jest protein koji je kod ljudi kodiran genom XPC sa p kraka hromosoma 3. XPC je uključen u prepoznavanje glomaznih DNK adukata u popravkama putem ekscizije nukleotida.^[4] It is located on chromosome 3.^[5]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 940 aminokiselina, a molekulska težina 105.953 Da.^[4]

• 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

10		20		30		40		50
MARKRAAGGE		PRGRELRSQK		SKAKSKARRE		EEEEDAFEDE		KPPKKSLLSK
VSQGKRKRGC		SHPGGSADGP		AKKKVAKVTV		KSENLKVIKD		EALSDGDDLR
DFPSDLKKAH		HLKRGATMNE		DSNEEEEESE		NDWEEVEELS		EPVLGDVRES
TAFSRSLLPV		KPVEIEIETP		EQAKTRERSE		KIKLEFETYL		RRAMKRFNKG
VHEDTHKVHL		LCLLANGFYR		NNICSQPDLH		AIGLSIIPAR		FTRVLPRDVD
TYYLSNLVKW		FIGTFTVNAE		LSASEQDNLQ		TTLERRFAIY		SARDDEELVH
IFLLILRALQ		LLTRLVLSLQ		PIPLKSATAK		GKKPSKERLT		ADPGGSSETS
SQVLENHTKP		KTSKGTKQEE		TFAKGTCRPS		AKGKRNKGGR		KKRSKPSSSE
EDEGPGDKQE		KATQRRPHGR		ERRVASRVSY		KEESGSDEAG		SGSDFELSSG
EASDPSDEDS		EPGPPKQRKA		PAPQRTKAGS		KSASRTHRGS		HRKDPSLPAA
SSSSSSSKRG		KKMCSDGEKA		EKRSIAGIDQ		WLEVFCEQEE		KWVCVDCVHG
VVGQPLTCYK		YATKPMTYVV		GIDSDGWVRD		VTQRYDPVWM		TVTRKCRVDA
EWWAETLRPY		QSPFMDREKK		EDLEFQAKHM		DQPLPTAIGL		YKNHPLYALK
RHLLKYEAIY		PETAAILGYC		RGEAVYSRDC		VHTLHSRDTW		LKKARVVRLG
EVPYKMVKGF		SNRARKARLA		EPQLREENDL		GLFGYWQTEE		YQPPVAVDGK
VPRNEFGNVY		LFLPSMMPIG		CVQLNLPNLH		RVARKLDIDC		VQAITGFDFH
GGYSHPVTDG		YIVCEEFKDV		LLTAWENEQA		VIERKEKEKK		EKRALGNWKL
LAKGLLIRER		LKRRYGPKSE		AAAPHTDAGG		GLSSDEEEGT		SSQAEAARIL
AASWPQNRED		EEKQKLKGGP		KKTKREKKAA		ASHLFPFEQL

Funkcija

Ovaj gen kodira komponentu (NER) puta popravka nukleotidne ekscizijske. Postoji više komponenti uključenih u NER put, uključujući Xeroderma pigmentosum (XP) A-G i V, Cockayneov sindrom (CS) A i B, i trihotiodistrofijsku (TTD) grupu A, itd. Ova komponenta, XPC, ima važnu ulogu u ranim koracima globalnog genoma NER, posebno u prepoznavanju oštećenja, formiranju otvorenog kompleksa i popravljanju formiranja kompleksa proteina.^[4]

Kompleks XPC-RAD23B je početni faktor prepoznavanja oštećenja u globalnoj popravci ekscizijom genomskih nukleotida (GG-NER)).^[6] XPC-RAD23B prepoznaje širok spektar lezija koje termodinamički destabiliziraju DNK duplekse, uključujući UV-inducirane fotoproizvode (ciklopirimidinski dimeri i 6-4 fotoproizvodi), adukte formirane mutagenima iz okoliša kao što su benzo[a]piren ili različiti aromatski amini, određene oksidativne endogene lezije kao što su ciklopurini i adukti formirani hemoterapijskim lijekovima protiv raka kao što je cisplatin. Prisustvo XPC-RAD23B je potrebno za sklapanje drugih jedarnih faktora NER i progresiju kroz NER put i in vitro i in vivo.^[7] Iako je većina studija sprovedena sa XPC-RAD23B, on je dio trimernog kompleksa sa centrinom-2, proteinom koji vezuje kalcij iz porodice kalmodulina.^[7]

Klinički značaj

Mutacije ovog gena ili nekih drugih komponenti NER-a rezultiraju bolešću Xeroderma pigmentosum, rijetkim autosomno recesivnim poremećajem koji karakterizira povećana osjetljivost na sunčevu svjetlost s razvojem karcinoma u ranoj dobi.^[4]

Rak

Čini se da je oštećenje DNK primarni uzrok kancera,^[8] a nedostaci gena za popravak DNK vjerovatno su u osnovi mnogih oblika raka.^[9][10] Ako je popravak DNK nedovoljan, oštećenje DNK ima tendenciju da se akumulira. Takvo prekomjerno oštećenje DNK može povećati mutacije zbog sklonosti greškama translezijskim sintezama. Prekomjerno oštećenje DNK također može povećati epigenetičke promjene zbog grešaka tokom popravka DNK.^[11][12] Takve mutacije i epigenetičke promjene mogu dovesti do raka.

Smanjenje ekspresije gena za popravak DNK (obično uzrokovano epigenetičkim promjenama kao što je hipermetilacija promotora) vrlo je česta pojava kod karcinoma i obično je mnogo češća od mutacijskih defekata u genima za popravak DNK kod karcinoma. Tabela ispod pokazuje da je ekspresija XPC često epigenetički smanjena kod raka mokraćne bešike, kao i kod raka pluća nemalih ćelija, a također pokazuje da je XPC češće smanjen u naprednijim fazama ovih bolesti.

Učestalost smanjene ekspresije XPC kod karcinoma, sa stadijima koji su posebno naznačeni

Kancer	Učestalost	Referenca
Rak mokraćne bešike	50%	[13]
Papilarna urotelna neoplazma niskog malignog potencijala	35%	[13]
Papilarni karcinom mokraćne bešike niskog stepena	42%	[13]
Papilarni rak mokraćne bešike visokog stepena	65%	[13]
Nemaloćelijski rak pluća (NSCLC)	70%	[14]
Stadij NSCLC	62%	[14]
Stadij NSCLCII-III	77%	[14]

Dok se pokazalo da je epigenetička hipermetilacija promotorskog regiona "XPC" gena povezana sa niskom ekspresijom XPC,^[13] drugi način epigenetičke represije "XPC" također se može pojaviti prekomjernom ekspresijom mikroRNK miR-890.^[15]

Interakcije

Pokazano je da XPC (gen) reaguje sa ABCA1,^[16] CETN2^[17] i XPB.^[18]

Reference

1. GRCm38: Ensembl release 89: ENSMUSG00000030094 - Ensembl, maj 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Entrez Gene: XPC xeroderma pigmentosum, complementation group C".
5. "OMIM Entry - # 278720 - XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP C; XPC". Pristupljeno 12. 12. 2014.
6. Sugasawa K, Ng JM, Masutani C, Iwai S, van der Spek PJ, Eker AP, Hanaoka F, Bootsma D, Hoeijmakers JH (1998). "Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair". Mol. Cell. 2 (2): 223–32. doi:10.1016/s1097-2765(00)80132-x. PMID 9734359.
7. Schärer OD (Oct 2013). "Nucleotide excision repair in eukaryotes". Cold Spring Harbor Perspectives in Biology. 5 (10): a012609. doi:10.1101/cshperspect.a012609. PMC 3783044. PMID 24086042.
8. Kastan MB (2008). "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Mol. Cancer Res. 6 (4): 517–24. doi:10.1158/1541-7786.MCR-08-0020. PMID 18403632.
9. Harper JW, Elledge SJ (2007). "The DNA damage response: ten years after". Mol. Cell. 28 (5): 739–45. doi:10.1016/j.molcel.2007.11.015. PMID 18082599.
10. Dietlein F, Reinhardt HC (2014). "Molecular pathways: exploiting tumor-specific molecular defects in DNA repair pathways for precision cancer therapy". Clin. Cancer Res. 20 (23): 5882–7. doi:10.1158/1078-0432.CCR-14-1165. PMID 25451105.
11. O'Hagan HM, Mohammad HP, Baylin SB (2008). "Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island". PLOS Genetics. 4 (8): e1000155. doi:10.1371/journal.pgen.1000155. PMC 2491723. PMID 18704159.
12. Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV (Jul 2007). "DNA damage, homology-directed repair, and DNA methylation". PLOS Genetics. 3 (7): e110. doi:10.1371/journal.pgen.0030110. PMC 1913100. PMID 17616978.
13. Yang J, Xu Z, Li J, Zhang R, Zhang G, Ji H, Song B, Chen Z (2010). "XPC epigenetic silence coupled with p53 alteration has a significant impact on bladder cancer outcome". J. Urol. 184 (1): 336–43. doi:10.1016/j.juro.2010.03.044. PMID 20488473.
14. Yeh KT, Wu YH, Lee MC, Wang L, Li CT, Chen CY, Lee H (2012). "XPC mRNA level may predict relapse in never-smokers with non-small cell lung cancers". Ann. Surg. Oncol. 19 (3): 734–42. doi:10.1245/s10434-011-1992-9. PMID 21861227. S2CID 19154489.
15. Hatano K, Kumar B, Zhang Y, Coulter JB, Hedayati M, Mears B, Ni X, Kudrolli TA, Chowdhury WH, Rodriguez R, DeWeese TL, Lupold SE (2015). "A functional screen identifies miRNAs that inhibit DNA repair and sensitize prostate cancer cells to ionizing radiation". Nucleic Acids Res. 43 (8): 4075–86. doi:10.1093/nar/gkv273. PMC 4417178. PMID 25845598.
16. Shimizu Y, Iwai S, Hanaoka F, Sugasawa K (januar 2003). "Xeroderma pigmentosum group C protein interacts physically and functionally with thymine DNA glycosylase". EMBO J. 22 (1): 164–73. doi:10.1093/emboj/cdg016. PMC 140069. PMID 12505994.
17. Araki M, Masutani C, Takemura M, Uchida A, Sugasawa K, Kondoh J, Ohkuma Y, Hanaoka F (juni 2001). "Centrosome protein centrin 2/caltractin 1 is part of the xeroderma pigmentosum group C complex that initiates global genome nucleotide excision repair". J. Biol. Chem. 276 (22): 18665–72. doi:10.1074/jbc.M100855200. PMID 11279143.
18. Yokoi M, Masutani C, Maekawa T, Sugasawa K, Ohkuma Y, Hanaoka F (mart 2000). "The xeroderma pigmentosum group C protein complex XPC-HR23B plays an important role in the recruitment of transcription factor IIH to damaged DNA". J. Biol. Chem. 275 (13): 9870–5. doi:10.1074/jbc.275.13.9870. PMID 10734143.

Dopunska literatura

• Cleaver JE, Thompson LH, Richardson AS, States JC (1999). "A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy". Hum. Mutat. 14 (1): 9–22. doi:10.1002/(SICI)1098-1004(1999)14:1<9::AID-HUMU2>3.0.CO;2-6. PMID 10447254. S2CID 24148589.
• El-Deiry WS (2003). "Transactivation of repair genes by BRCA1". Cancer Biol. Ther. 1 (5): 490–1. doi:10.4161/cbt.1.5.162. PMID 12496474.
• Sugasawa K (2007). "UV-induced ubiquitylation of XPC complex, the UV-DDB-ubiquitin ligase complex, and DNA repair". J. Mol. Histol. 37 (5–7): 189–202. doi:10.1007/s10735-006-9044-7. PMID 16858626. S2CID 817898.
• Legerski R, Peterson C (1993). "Expression cloning of a human DNA repair gene involved in xeroderma pigmentosum group C". Nature. 360 (6404): 610. doi:10.1038/360610b0. PMID 1461286.
• Legerski R, Peterson C (1992). "Expression cloning of a human DNA repair gene involved in xeroderma pigmentosum group C". Nature. 359 (6390): 70–3. Bibcode:1992Natur.359...70L. doi:10.1038/359070a0. PMID 1522891. S2CID 34276965.
• Legerski RJ, Liu P, Li L, Peterson CA, Zhao Y, Leach RJ, Naylor SL, Siciliano MJ (1994). "Assignment of xeroderma pigmentosum group C (XPC) gene to chromosome 3p25". Genomics. 21 (1): 266–9. doi:10.1006/geno.1994.1256. PMID 8088800.
• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Masutani C, Sugasawa K, Yanagisawa J, Sonoyama T, Ui M, Enomoto T, Takio K, Tanaka K, van der Spek PJ, Bootsma D (1994). "Purification and cloning of a nucleotide excision repair complex involving the xeroderma pigmentosum group C protein and a human homologue of yeast RAD23". EMBO J. 13 (8): 1831–43. doi:10.1002/j.1460-2075.1994.tb06452.x. PMC 395023. PMID 8168482.
• Li L, Bales ES, Peterson CA, Legerski RJ (1994). "Characterization of molecular defects in xeroderma pigmentosum group C". Nat. Genet. 5 (4): 413–7. doi:10.1038/ng1293-413. PMID 8298653. S2CID 24923699.
• Li L, Peterson C, Legerski R (1996). "Sequence of the mouse XPC cDNA and genomic structure of the human XPC gene". Nucleic Acids Res. 24 (6): 1026–8. doi:10.1093/nar/24.6.1026. PMC 145764. PMID 8604333.
• van der Spek PJ, Eker A, Rademakers S, Visser C, Sugasawa K, Masutani C, Hanaoka F, Bootsma D, Hoeijmakers JH (1996). "XPC and human homologs of RAD23: intracellular localization and relationship to other nucleotide excision repair complexes". Nucleic Acids Res. 24 (13): 2551–9. doi:10.1093/nar/24.13.2551. PMC 145966. PMID 8692695.
• Li L, Lu X, Peterson C, Legerski R (1997). "XPC interacts with both HHR23B and HHR23A in vivo". Mutat. Res. 383 (3): 197–203. doi:10.1016/s0921-8777(97)00002-5. PMID 9164480.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Zeng L, Quilliet X, Chevallier-Lagente O, Eveno E, Sarasin A, Mezzina M (1998). "Retrovirus-mediated gene transfer corrects DNA repair defect of xeroderma pigmentosum cells of complementation groups A, B and C". Gene Ther. 4 (10): 1077–84. doi:10.1038/sj.gt.3300495. PMID 9415314.
• Khan SG, Levy HL, Legerski R, Quackenbush E, Reardon JT, Emmert S, Sancar A, Li L, Schneider TD, Cleaver JE, Kraemer KH (1998). "Xeroderma pigmentosum group C splice mutation associated with autism and hypoglycinemia". J. Invest. Dermatol. 111 (5): 791–6. doi:10.1046/j.1523-1747.1998.00391.x. PMID 9804340.
• Yokoi M, Masutani C, Maekawa T, Sugasawa K, Ohkuma Y, Hanaoka F (2000). "The xeroderma pigmentosum group C protein complex XPC-HR23B plays an important role in the recruitment of transcription factor IIH to damaged DNA". J. Biol. Chem. 275 (13): 9870–5. doi:10.1074/jbc.275.13.9870. PMID 10734143.
• Batty D, Rapic'-Otrin V, Levine AS, Wood RD (2000). "Stable binding of human XPC complex to irradiated DNA confers strong discrimination for damaged sites". J. Mol. Biol. 300 (2): 275–90. doi:10.1006/jmbi.2000.3857. PMID 10873465.
• Araújo SJ, Nigg EA, Wood RD (2001). "Strong functional interactions of TFIIH with XPC and XPG in human DNA nucleotide excision repair, without a preassembled repairosome". Mol. Cell. Biol. 21 (7): 2281–91. doi:10.1128/MCB.21.7.2281-2291.2001. PMC 86862. PMID 11259578.
• Araki M, Masutani C, Takemura M, Uchida A, Sugasawa K, Kondoh J, Ohkuma Y, Hanaoka F (2001). "Centrosome protein centrin 2/caltractin 1 is part of the xeroderma pigmentosum group C complex that initiates global genome nucleotide excision repair". J. Biol. Chem. 276 (22): 18665–72. doi:10.1074/jbc.M100855200. PMID 11279143.

Vanjski linkovi

• GeneReviews/NIH/NCBI/UW entry on Xeroderma Pigmentosum