XPC
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 uredi
Dužina polipeptidnog lanca je 940 aminokiselina, a molekulska težina 105.953 Da.[4]
| 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 uredi
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 uredi
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 uredi
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.
| 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 uredi
Pokazano je da XPC (gen) reaguje sa ABCA1,[16] CETN2[17] i XPB.[18]
Reference uredi
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030094 - 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 c d "Entrez Gene: XPC xeroderma pigmentosum, complementation group C".
- ^ "OMIM Entry - # 278720 - XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP C; XPC". Pristupljeno 12. 12. 2014.
- ^ 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.
- ^ a b 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ a b c d e 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.
- ^ a b c 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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 uredi
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- 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.
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- 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.
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- 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.