XPB — Mediated Wiki

{{Short description|Mammalian protein found in Homo sapiens}} {{Infobox_gene}} '''XPB''' (xeroderma pigmentosum type B) is an ATP-dependent DNA helicase in humans that is a part of the TFIIH transcription factor complex.

==Structure== The 3D-structure of the archaeal homolog of XPB has been solved by X-ray crystallography by Dr. John Tainer and his group at The Scripps Research Institute.<ref name=fan2006>{{cite journal |vauthors=Fan L, Arvai AS, Cooper PK, Iwai S, Hanaoka F, Tainer JA | title = Conserved XPB Core Structure and Motifs for DNA Unwinding: Implications for Pathway Selection of Transcription or Excision Repair | journal = Molecular Cell | volume = 22 | issue = 1 | pages = 27–37 | date = April 2006 | pmid = 16600867 | doi = 10.1016/j.molcel.2006.02.017 | doi-access = free }}</ref>

==Function== XPB plays a significant role in normal basal transcription, transcription coupled repair (TCR), and nucleotide excision repair (NER). Purified XPB has been shown to unwind DNA with 3’-5’ polarity.

The function of the XPB(ERCC3) protein in NER is to assist in unwinding the DNA double helix after damage is initially recognized. NER is a multi-step pathway that removes a wide range of different DNA damages that distort normal base pairing. Such damages include bulky chemical adducts, UV-induced pyrimidine dimers, and several forms of oxidative damage. Mutations in the XPB(ERCC3) gene can lead, in humans, to xeroderma pigmentosum (XP) or XP combined with Cockayne syndrome (XPCS).<ref name="pmid16947863">{{cite journal |vauthors=Oh KS, Khan SG, Jaspers NG, Raams A, Ueda T, Lehmann A, Friedmann PS, Emmert S, Gratchev A, Lachlan K, Lucassan A, Baker CC, Kraemer KH |title=Phenotypic heterogeneity in the XPB DNA helicase gene (ERCC3): xeroderma pigmentosum without and with Cockayne syndrome |journal=Hum. Mutat. |volume=27 |issue=11 |pages=1092–103 |year=2006 |pmid=16947863 |doi=10.1002/humu.20392 |s2cid=22852219 |doi-access=free }}</ref> Mutant XPB cells from individuals with the XPCS phenotype are sensitive to UV irradiation and acute oxidative stress.<ref name="pmid19114557">{{cite journal |vauthors=Andressoo JO, Weeda G, de Wit J, Mitchell JR, Beems RB, van Steeg H, van der Horst GT, Hoeijmakers JH |title=An Xpb mouse model for combined xeroderma pigmentosum and cockayne syndrome reveals progeroid features upon further attenuation of DNA repair |journal=Mol. Cell. Biol. |volume=29 |issue=5 |pages=1276–90 |year=2009 |pmid=19114557 |pmc=2643825 |doi=10.1128/MCB.01229-08 }}</ref>

XPB helicase is also a component of the p53-mediated programmed cell death (apoptosis) pathway.<ref>{{cite journal |vauthors=Wang XW, Vermeulen W, Coursen JD, Gibson M, Lupold SE, Forrester K, Xu G, Elmore L, Yeh H, Hoeijmakers JH, Harris CC |title=The XPB and XPD DNA helicases are components of the p53-mediated apoptosis pathway |journal=Genes Dev |volume=10 |issue=10 |pages=1219–32 |date=May 1996 |pmid=8675009 |doi=10.1101/gad.10.10.1219 |url=|hdl=1765/3094 |hdl-access=free }}</ref>

==Disorders== Mutations in XPB and other related complementation groups, XPA-XPG, leads to a number of genetic disorders such as Xeroderma pigmentosum, Cockayne's syndrome, and trichothiodystrophy.

==Interactions== XPB has been shown to interact with: {{div col|colwidth=20em}} * BCR gene,<ref name = pmid9874796>{{cite journal |vauthors=Takeda N, Shibuya M, Maru Y | title = The BCR-ABL oncoprotein potentially interacts with the xeroderma pigmentosum group B protein | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 1 | pages = 203–7 | date = January 1999 | pmid = 9874796 | pmc = 15117 | doi = 10.1073/pnas.96.1.203 | bibcode = 1999PNAS...96..203T | doi-access = free }}</ref> * CDK7,<ref name = pmid15220921/><ref name = pmid9130708/><ref name = pmid8521393>{{cite journal |vauthors=Yee A, Nichols MA, Wu L, Hall FL, Kobayashi R, Xiong Y | title = Molecular cloning of CDK7-associated human MAT1, a cyclin-dependent kinase-activating kinase (CAK) assembly factor | journal = Cancer Res. | volume = 55 | issue = 24 | pages = 6058–62 | date = December 1995 | pmid = 8521393 }}</ref> * ERCC2,<ref name = pmid15220921>{{cite journal |vauthors=Giglia-Mari G, Coin F, Ranish JA, Hoogstraten D, Theil A, Wijgers N, Jaspers NG, Raams A, Argentini M, van der Spek PJ, Botta E, Stefanini M, Egly JM, Aebersold R, Hoeijmakers JH, Vermeulen W | title = A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A | journal = Nat. Genet. | volume = 36 | issue = 7 | pages = 714–9 | date = July 2004 | pmid = 15220921 | doi = 10.1038/ng1387 | doi-access = free }}</ref><ref name = pmid9118947>{{cite journal |vauthors=Marinoni JC, Roy R, Vermeulen W, Miniou P, Lutz Y, Weeda G, Seroz T, Gomez DM, Hoeijmakers JH, Egly JM | title = Cloning and characterization of p52, the fifth subunit of the core of the transcription/DNA repair factor TFIIH | journal = EMBO J. | volume = 16 | issue = 5 | pages = 1093–102 | date = March 1997 | pmid = 9118947 | pmc = 1169708 | doi = 10.1093/emboj/16.5.1093 }}</ref><ref name = pmid8152490>{{cite journal |vauthors=Drapkin R, Reardon JT, Ansari A, Huang JC, Zawel L, Ahn K, Sancar A, Reinberg D | title = Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II | journal = Nature | volume = 368 | issue = 6473 | pages = 769–72 | date = April 1994 | pmid = 8152490 | doi = 10.1038/368769a0 | bibcode = 1994Natur.368..769D | s2cid = 4363484 }}</ref><ref name = pmid8652557>{{cite journal |vauthors=Iyer N, Reagan MS, Wu KJ, Canagarajah B, Friedberg EC | title = Interactions involving the human RNA polymerase II transcription/nucleotide excision repair complex TFIIH, the nucleotide excision repair protein XPG, and Cockayne syndrome group B (CSB) protein | journal = Biochemistry | volume = 35 | issue = 7 | pages = 2157–67 | date = February 1996 | pmid = 8652557 | doi = 10.1021/bi9524124 }}</ref> * GTF2H1,<ref name = pmid15220921/><ref name = pmid9130708>{{cite journal |vauthors=Rossignol M, Kolb-Cheynel I, Egly JM | title = Substrate specificity of the cdk-activating kinase (CAK) is altered upon association with TFIIH | journal = EMBO J. | volume = 16 | issue = 7 | pages = 1628–37 | date = April 1997 | pmid = 9130708 | pmc = 1169767 | doi = 10.1093/emboj/16.7.1628 }}</ref><ref name = pmid9118947/> * GTF2H2,<ref name = pmid15220921/><ref name = pmid9118947/> * GTF2H4,<ref name = pmid15220921/><ref name = pmid9118947/> * GTF2H5,<ref name = pmid15220921/> * P53,<ref name = pmid7663514>{{cite journal |vauthors=Wang XW, Yeh H, Schaeffer L, Roy R, Moncollin V, Egly JM, Wang Z, Freidberg EC, Evans MK, Taffe BG | title = p53 modulation of TFIIH-associated nucleotide excision repair activity | journal = Nat. Genet. | volume = 10 | issue = 2 | pages = 188–95 | date = June 1995 | pmid = 7663514 | doi = 10.1038/ng0695-188 | s2cid = 38325851 | url = http://repub.eur.nl/pub/54884 | hdl = 1765/54884 | hdl-access = free }}</ref> * PSMC5,<ref name = pmid9173976>{{cite journal | vauthors = Weeda G, Rossignol M, Fraser RA, Winkler GS, Vermeulen W, van 't Veer LJ, Ma L, Hoeijmakers JH, Egly JM | author6-link = Laura J. van't Veer | title = The XPB subunit of repair/transcription factor TFIIH directly interacts with SUG1, a subunit of the 26S proteasome and putative transcription factor | journal = Nucleic Acids Res. | volume = 25 | issue = 12 | pages = 2274–83 | date = June 1997 | pmid = 9173976 | pmc = 146752 | doi = 10.1093/nar/25.12.2274 }}</ref> and * XPC.<ref name = pmid10734143>{{cite journal |vauthors=Yokoi M, Masutani C, Maekawa T, Sugasawa K, Ohkuma Y, Hanaoka F | title = The xeroderma pigmentosum group C protein complex XPC-HR23B plays an important role in the recruitment of transcription factor IIH to damaged DNA | journal = J. Biol. Chem. | volume = 275 | issue = 13 | pages = 9870–5 | date = March 2000 | pmid = 10734143 | doi = 10.1074/jbc.275.13.9870 | doi-access = free }}</ref> {{Div col end}}

==Small molecule inhibitors== Potent, bioactive natural products like triptolide that inhibit mammalian transcription via inhibition of the XPB subunit of the general transcription factor TFIIH has been recently reported as a glucose conjugate for targeting hypoxic cancer cells with increased glucose transporter expression.<ref>{{cite journal | journal = iScience | title = A Glucose-Triptolide Conjugate Selectively Targets Cancer Cells under Hypoxia | volume = 23 | issue = 9 | year = 2020 |vauthors=Datan E, Minn I, Peng X, He QL, Ahn H, Yu B, Pomper MG, Liu JO | article-number = 101536 | pmid = 33083765 | doi=10.1016/j.isci.2020.101536| pmc = 7509213 | bibcode = 2020iSci...23j1536D | doi-access = free }}</ref>

==See also== * XP {{Clear}}

==References== {{reflist|35em}}

==Further reading== {{refbegin|35em}} *{{cite journal | author = Jeang KT | title = Tat, Tat-associated kinase, and transcription. | journal = J. Biomed. Sci. | volume = 5 | issue = 1 | pages = 24–7 | year = 1998 | pmid = 9570510 | doi = 10.1007/BF02253352 }} *{{cite journal |vauthors=Yankulov K, Bentley D | title = Transcriptional control: Tat cofactors and transcriptional elongation. | journal = Curr. Biol. | volume = 8 | issue = 13 | pages = R447–9 | year = 1998 | pmid = 9651670 | doi = 10.1016/S0960-9822(98)70289-1 | s2cid = 15480646 | doi-access = free | bibcode = 1998CBio....8.R447Y }} *{{cite journal |vauthors=Cleaver JE, Thompson LH, Richardson AS, States JC | title = A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. | journal = Hum. Mutat. | volume = 14 | issue = 1 | pages = 9–22 | year = 1999 | pmid = 10447254 | doi = 10.1002/(SICI)1098-1004(1999)14:1<9::AID-HUMU2>3.0.CO;2-6 | s2cid = 24148589 | doi-access = free }} *{{cite journal |vauthors=Ma L, Weeda G, Jochemsen AG, Bootsma D, Hoeijmakers JH, van der Eb AJ | title = Molecular and functional analysis of the XPBC/ERCC-3 promoter: transcription activity is dependent on the integrity of an Sp1-binding site. | journal = Nucleic Acids Res. | volume = 20 | issue = 2 | pages = 217–24 | year = 1992 | pmid = 1741247 | pmc = 310357 | doi = 10.1093/nar/20.2.217 }} *{{cite journal |vauthors=Weeda G, Wiegant J, van der Ploeg M, Geurts van Kessel AH, van der Eb AJ, Hoeijmakers JH | title = Localization of the xeroderma pigmentosum group B-correcting gene ERCC3 to human chromosome 2q21. | journal = Genomics | volume = 10 | issue = 4 | pages = 1035–1040 | year = 1991 | pmid = 1916809 | doi = 10.1016/0888-7543(91)90195-K | url = http://repub.eur.nl/pub/3025 | hdl = 1765/3025 | hdl-access = free }} *{{cite journal |vauthors=Weeda G, Ma LB, van Ham RC, van der Eb AJ, Hoeijmakers JH | title = Structure and expression of the human XPBC/ERCC-3 gene involved in DNA repair disorders xeroderma pigmentosum and Cockayne's syndrome. | journal = Nucleic Acids Res. | volume = 19 | issue = 22 | pages = 6301–6308 | year = 1991 | pmid = 1956789 | pmc = 329143 | doi = 10.1093/nar/19.22.6301 }} *{{cite journal |vauthors=Weeda G, van Ham RC, Masurel R, Westerveld A, Odijk H, de Wit J, Bootsma D, van der Eb AJ, Hoeijmakers JH | title = Molecular cloning and biological characterization of the human excision repair gene ERCC-3. | journal = Mol. Cell. Biol. | volume = 10 | issue = 6 | pages = 2570–2581 | year = 1990 | pmid = 2111438 | pmc = 360615 | doi = 10.1128/MCB.10.6.2570}} *{{cite journal |vauthors=Weeda G, van Ham RC, Vermeulen W, Bootsma D, van der Eb AJ, Hoeijmakers JH | title = A presumed DNA helicase encoded by ERCC-3 is involved in the human repair disorders xeroderma pigmentosum and Cockayne's syndrome. | journal = Cell | volume = 62 | issue = 4 | pages = 777–91 | year = 1990 | pmid = 2167179 | doi = 10.1016/0092-8674(90)90122-U | url = http://repub.eur.nl/pub/3020 | hdl = 1765/3020 | s2cid = 31743602 | hdl-access = free }} *{{cite journal |vauthors=Wang XW, Yeh H, Schaeffer L, Roy R, Moncollin V, Egly JM, Wang Z, Freidberg EC, Evans MK, Taffe BG | title = p53 modulation of TFIIH-associated nucleotide excision repair activity. | journal = Nat. Genet. | volume = 10 | issue = 2 | pages = 188–95 | year = 1995 | pmid = 7663514 | doi = 10.1038/ng0695-188 | s2cid = 38325851 | url = http://repub.eur.nl/pub/54884 | hdl = 1765/54884 | hdl-access = free }} *{{cite journal |vauthors=Maxon ME, Goodrich JA, Tjian R | title = Transcription factor IIE binds preferentially to RNA polymerase IIa and recruits TFIIH: a model for promoter clearance. | journal = Genes Dev. | volume = 8 | issue = 5 | pages = 515–24 | year = 1994 | pmid = 7926747 | doi = 10.1101/gad.8.5.515 | doi-access = free }} *{{cite journal |vauthors=Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–4 | year = 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }} *{{cite journal |vauthors=Drapkin R, Reardon JT, Ansari A, Huang JC, Zawel L, Ahn K, Sancar A, Reinberg D | title = Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II | journal = Nature | volume = 368 | issue = 6473 | pages = 769–72 | year = 1994 | pmid = 8152490 | doi = 10.1038/368769a0 | bibcode = 1994Natur.368..769D | s2cid = 4363484 }} *{{cite journal |vauthors=van Vuuren AJ, Vermeulen W, Ma L, Weeda G, Appeldoorn E, Jaspers NG, van der Eb AJ, Bootsma D, Hoeijmakers JH, Humbert S | title = Correction of xeroderma pigmentosum repair defect by basal transcription factor BTF2 (TFIIH) | journal = EMBO J. | volume = 13 | issue = 7 | pages = 1645–1653 | year = 1994 | pmid = 8157004 | pmc = 394995 | doi = 10.1002/j.1460-2075.1994.tb06428.x}} *{{cite journal |vauthors=Schaeffer L, Moncollin V, Roy R, Staub A, Mezzina M, Sarasin A, Weeda G, Hoeijmakers JH, Egly JM | title = The ERCC2/DNA repair protein is associated with the class II BTF2/TFIIH transcription factor | journal = EMBO J. | volume = 13 | issue = 10 | pages = 2388–2392 | year = 1994 | pmid = 8194528 | pmc = 395103 | doi = 10.1002/j.1460-2075.1994.tb06522.x}} *{{cite journal |vauthors=Guzder SN, Sung P, Bailly V, Prakash L, Prakash S | title = RAD25 is a DNA helicase required for DNA repair and RNA polymerase II transcription | journal = Nature | volume = 369 | issue = 6481 | pages = 578–81 | year = 1994 | pmid = 8202161 | doi = 10.1038/369578a0 | bibcode = 1994Natur.369..578G | s2cid = 4332757 }} *{{cite journal |vauthors=Vermeulen W, Scott RJ, Rodgers S, Müller HJ, Cole J, Arlett CF, Kleijer WJ, Bootsma D, Hoeijmakers JH, Weeda G | title = Clinical heterogeneity within xeroderma pigmentosum associated with mutations in the DNA repair and transcription gene ERCC3 | journal = Am. J. Hum. Genet. | volume = 54 | issue = 2 | pages = 191–200 | year = 1994 | pmid = 8304337 | pmc = 1918172 }} *{{cite journal |vauthors=Scott RJ, Itin P, Kleijer WJ, Kolb K, Arlett C, Muller H | title = Xeroderma pigmentosum-Cockayne syndrome complex in two patients: absence of skin tumors despite severe deficiency of DNA excision repair | journal = J. Am. Acad. Dermatol. | volume = 29 | issue = 5 Pt 2 | pages = 883–9 | year = 1993 | pmid = 8408834 | doi = 10.1016/0190-9622(93)70263-S }} *{{cite journal |vauthors=Blau J, Xiao H, McCracken S, O'Hare P, Greenblatt J, Bentley D | title = Three functional classes of transcriptional activation domain | journal = Mol. Cell. Biol. | volume = 16 | issue = 5 | pages = 2044–2055 | year = 1996 | pmid = 8628270 | pmc = 231191 | doi = 10.1128/MCB.16.5.2044}} *{{cite journal |vauthors=Iyer N, Reagan MS, Wu KJ, Canagarajah B, Friedberg EC | title = Interactions involving the human RNA polymerase II transcription/nucleotide excision repair complex TFIIH, the nucleotide excision repair protein XPG, and Cockayne syndrome group B (CSB) protein | journal = Biochemistry | volume = 35 | issue = 7 | pages = 2157–2167 | year = 1996 | pmid = 8652557 | doi = 10.1021/bi9524124 }} *{{cite journal |vauthors=Hwang JR, Moncollin V, Vermeulen W, Seroz T, van Vuuren H, Hoeijmakers JH, Egly JM | title = A 3' → 5' XPB helicase defect in repair/transcription factor TFIIH of xeroderma pigmentosum group B affects both DNA repair and transcription | journal = J. Biol. Chem. | volume = 271 | issue = 27 | pages = 15898–904 | year = 1996 | pmid = 8663148 | doi = 10.1074/jbc.271.27.15898 | doi-access = free | hdl = 1765/3098 | hdl-access = free }} {{refend}}

==External links== * [https://www.ncbi.nlm.nih.gov/books/NBK1397/ GeneReviews/NIH/NCBI/UW entry on Xeroderma Pigmentosum] * {{MeshName|XPBC-ERCC-3+protein}}

{{DEFAULTSORT:Xpb}} Category:EC 3.6.4 Category:DNA replication Category:Helicases