XPB

ERCC3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4ERN, 5IY9, 5IVW, 5IY7, 5IY8, 5IY6
Identifiers
Aliases	ERCC3 , excision repair cross-complementation group 3, BTF2, GTF2H, RAD25, TFIIH, XPB, TTD2, ERCC excision repair 3, TFIIH core complex helicase subunit, Ssl2
External IDs	OMIM: 133510; MGI: 95414; HomoloGene: 96; GeneCards: ERCC3; OMA:ERCC3 - orthologs
Gene location (Human) Chr. Chromosome 2 (human) [1] Band 2q14.3 Start 127,257,290 bp [1] End 127,294,166 bp [1]
Gene location (Mouse) Chr. Chromosome 18 (mouse) [2] Band 18|18 B1 Start 32,373,353 bp [2] End 32,403,204 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in sural nerve right hemisphere of cerebellum right uterine tube gastric mucosa gonad granulocyte ganglionic eminence body of uterus anterior pituitary canal of the cervix Top expressed in spermatid renal corpuscle granulocyte endothelial cell of lymphatic vessel ventricular zone epiblast tail of embryo medullary collecting duct lumbar spinal ganglion yolk sac More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein C-terminus binding nucleotide binding DNA helicase activity protein kinase activity hydrolase activity ATP-dependent activity, acting on DNA protein N-terminus binding 3'-5' DNA helicase activity ATP binding damaged DNA binding DNA binding transcription factor binding protein binding helicase activity RNA polymerase II CTD heptapeptide repeat kinase activity ATPase activity DNA translocase activity Cellular component transcription factor TFIIH core complex nucleus nucleoplasm transcription factor TFIIH holo complex transcription factor TFIID complex nucleotide-excision repair factor 3 complex transcription preinitiation complex Biological process response to hypoxia termination of RNA polymerase I transcription embryonic organ development transcription, DNA-templated response to UV 7-methylguanosine mRNA capping nucleotide-excision repair, DNA incision regulation of mitotic cell cycle phase transition apoptotic process positive regulation of apoptotic process protein phosphorylation hair cell differentiation response to oxidative stress UV protection cellular response to DNA damage stimulus transcription initiation from RNA polymerase II promoter global genome nucleotide-excision repair protein localization transcription elongation from RNA polymerase II promoter regulation of transcription, DNA-templated positive regulation of transcription by RNA polymerase II DNA topological change transcription initiation from RNA polymerase I promoter transcription by RNA polymerase II transcription-coupled nucleotide-excision repair nucleotide-excision repair nucleotide-excision repair, preincision complex stabilization DNA repair viral process nucleotide-excision repair, preincision complex assembly nucleotide-excision repair, DNA incision, 5'-to lesion nucleotide-excision repair, DNA duplex unwinding regulation of mitotic recombination promoter clearance from RNA polymerase II promoter transcription open complex formation at RNA polymerase II promoter regulation of transposition, RNA-mediated phosphorylation of RNA polymerase II C-terminal domain regulation of RNA polymerase II regulatory region sequence-specific DNA binding nucleotide-excision repair, DNA incision, 3'-to lesion transcription elongation from RNA polymerase I promoter Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2071 13872 Ensembl ENSG00000163161 ENSMUSG00000024382 UniProt P19447 P49135 RefSeq (mRNA) NM_000122 NM_001303416 NM_001303418 NM_133658 RefSeq (protein) NP_000113 NP_001290345 NP_001290347 NP_598419 Location (UCSC) Chr 2: 127.26 – 127.29 Mb Chr 18: 32.37 – 32.4 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. ^[5]

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). ^[6] Mutant XPB cells from individuals with the XPCS phenotype are sensitive to UV irradiation and acute oxidative stress. ^[7]

XPB helicase is also a component of the p53-mediated programmed cell death (apoptosis) pathway. ^[8]

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:

• BCR gene, ^[9]
• CDK7, ^{[10] [11] [12]}
• ERCC2, ^{[10] [13] [14] [15]}
• GTF2H1, ^{[10] [11] [13]}
• GTF2H2, ^{[10] [13]}
• GTF2H4, ^{[10] [13]}
• GTF2H5, ^[10]
• P53, ^[16]
• PSMC5, ^[17] and
• XPC. ^[18]

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. ^[19]

See also

• XP

References

1. GRCh38: Ensembl release 89: ENSG00000163161 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024382 – Ensembl, May 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.
5. Fan L, Arvai AS, Cooper PK, Iwai S, Hanaoka F, Tainer JA (April 2006). "Conserved XPB Core Structure and Motifs for DNA Unwinding: Implications for Pathway Selection of Transcription or Excision Repair". Molecular Cell. 22 (1): 27–37. doi: 10.1016/j.molcel.2006.02.017 . PMID   16600867.
6. 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 (2006). "Phenotypic heterogeneity in the XPB DNA helicase gene (ERCC3): xeroderma pigmentosum without and with Cockayne syndrome". Hum. Mutat. 27 (11): 1092–103. doi: 10.1002/humu.20392 . PMID   16947863. S2CID   22852219.
7. Andressoo JO, Weeda G, de Wit J, Mitchell JR, Beems RB, van Steeg H, van der Horst GT, Hoeijmakers JH (2009). "An Xpb mouse model for combined xeroderma pigmentosum and cockayne syndrome reveals progeroid features upon further attenuation of DNA repair". Mol. Cell. Biol. 29 (5): 1276–90. doi:10.1128/MCB.01229-08. PMC   2643825 . PMID   19114557.
8. Wang XW, Vermeulen W, Coursen JD, Gibson M, Lupold SE, Forrester K, Xu G, Elmore L, Yeh H, Hoeijmakers JH, Harris CC (May 1996). "The XPB and XPD DNA helicases are components of the p53-mediated apoptosis pathway". Genes Dev. 10 (10): 1219–32. doi:10.1101/gad.10.10.1219. hdl: 1765/3094 . PMID   8675009.
9. Takeda N, Shibuya M, Maru Y (January 1999). "The BCR-ABL oncoprotein potentially interacts with the xeroderma pigmentosum group B protein". Proc. Natl. Acad. Sci. U.S.A. 96 (1): 203–7. Bibcode:1999PNAS...96..203T. doi: 10.1073/pnas.96.1.203 . PMC   15117 . PMID   9874796.
10. 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 (July 2004). "A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A". Nat. Genet. 36 (7): 714–9. doi: 10.1038/ng1387 . PMID   15220921.
11. Rossignol M, Kolb-Cheynel I, Egly JM (April 1997). "Substrate specificity of the cdk-activating kinase (CAK) is altered upon association with TFIIH". EMBO J. 16 (7): 1628–37. doi:10.1093/emboj/16.7.1628. PMC   1169767 . PMID   9130708.
12. Yee A, Nichols MA, Wu L, Hall FL, Kobayashi R, Xiong Y (December 1995). "Molecular cloning of CDK7-associated human MAT1, a cyclin-dependent kinase-activating kinase (CAK) assembly factor". Cancer Res. 55 (24): 6058–62. PMID   8521393.
13. Marinoni JC, Roy R, Vermeulen W, Miniou P, Lutz Y, Weeda G, Seroz T, Gomez DM, Hoeijmakers JH, Egly JM (March 1997). "Cloning and characterization of p52, the fifth subunit of the core of the transcription/DNA repair factor TFIIH". EMBO J. 16 (5): 1093–102. doi:10.1093/emboj/16.5.1093. PMC   1169708 . PMID   9118947.
14. Drapkin R, Reardon JT, Ansari A, Huang JC, Zawel L, Ahn K, Sancar A, Reinberg D (April 1994). "Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II". Nature. 368 (6473): 769–72. Bibcode:1994Natur.368..769D. doi:10.1038/368769a0. PMID   8152490. S2CID   4363484.
15. Iyer N, Reagan MS, Wu KJ, Canagarajah B, Friedberg EC (February 1996). "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". Biochemistry. 35 (7): 2157–67. doi:10.1021/bi9524124. PMID   8652557.
16. Wang XW, Yeh H, Schaeffer L, Roy R, Moncollin V, Egly JM, Wang Z, Freidberg EC, Evans MK, Taffe BG (June 1995). "p53 modulation of TFIIH-associated nucleotide excision repair activity". Nat. Genet. 10 (2): 188–95. doi:10.1038/ng0695-188. hdl: 1765/54884 . PMID   7663514. S2CID   38325851.
17. Weeda G, Rossignol M, Fraser RA, Winkler GS, Vermeulen W, van 't Veer LJ, Ma L, Hoeijmakers JH, Egly JM (June 1997). "The XPB subunit of repair/transcription factor TFIIH directly interacts with SUG1, a subunit of the 26S proteasome and putative transcription factor". Nucleic Acids Res. 25 (12): 2274–83. doi:10.1093/nar/25.12.2274. PMC   146752 . PMID   9173976.
18. Yokoi M, Masutani C, Maekawa T, Sugasawa K, Ohkuma Y, Hanaoka F (March 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.
19. Datan E, Minn I, Peng X, He QL, Ahn H, Yu B, Pomper MG, Liu JO (2020). "A Glucose-Triptolide Conjugate Selectively Targets Cancer Cells under Hypoxia". iScience. 23 (9): 101536. Bibcode:2020iSci...23j1536D. doi: 10.1016/j.isci.2020.101536 . PMC   7509213 . PMID   33083765.

Further reading

• Jeang KT (1998). "Tat, Tat-associated kinase, and transcription". J. Biomed. Sci. 5 (1): 24–7. doi:10.1007/BF02253352. PMID   9570510.
• Yankulov K, Bentley D (1998). "Transcriptional control: Tat cofactors and transcriptional elongation". Curr. Biol. 8 (13): R447–9. Bibcode:1998CBio....8.R447Y. doi: 10.1016/S0960-9822(98)70289-1 . PMID   9651670. S2CID   15480646.
• 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.
• Ma L, Weeda G, Jochemsen AG, Bootsma D, Hoeijmakers JH, van der Eb AJ (1992). "Molecular and functional analysis of the XPBC/ERCC-3 promoter: transcription activity is dependent on the integrity of an Sp1-binding site". Nucleic Acids Res. 20 (2): 217–24. doi:10.1093/nar/20.2.217. PMC   310357 . PMID   1741247.
• Weeda G, Wiegant J, van der Ploeg M, Geurts van Kessel AH, van der Eb AJ, Hoeijmakers JH (1991). "Localization of the xeroderma pigmentosum group B-correcting gene ERCC3 to human chromosome 2q21". Genomics. 10 (4): 1035–1040. doi:10.1016/0888-7543(91)90195-K. hdl: 1765/3025 . PMID   1916809.
• Weeda G, Ma LB, van Ham RC, van der Eb AJ, Hoeijmakers JH (1991). "Structure and expression of the human XPBC/ERCC-3 gene involved in DNA repair disorders xeroderma pigmentosum and Cockayne's syndrome". Nucleic Acids Res. 19 (22): 6301–6308. doi:10.1093/nar/19.22.6301. PMC   329143 . PMID   1956789.
• Weeda G, van Ham RC, Masurel R, Westerveld A, Odijk H, de Wit J, Bootsma D, van der Eb AJ, Hoeijmakers JH (1990). "Molecular cloning and biological characterization of the human excision repair gene ERCC-3". Mol. Cell. Biol. 10 (6): 2570–2581. doi:10.1128/MCB.10.6.2570. PMC   360615 . PMID   2111438.
• Weeda G, van Ham RC, Vermeulen W, Bootsma D, van der Eb AJ, Hoeijmakers JH (1990). "A presumed DNA helicase encoded by ERCC-3 is involved in the human repair disorders xeroderma pigmentosum and Cockayne's syndrome". Cell. 62 (4): 777–91. doi:10.1016/0092-8674(90)90122-U. hdl: 1765/3020 . PMID   2167179. S2CID   31743602.
• Wang XW, Yeh H, Schaeffer L, Roy R, Moncollin V, Egly JM, Wang Z, Freidberg EC, Evans MK, Taffe BG (1995). "p53 modulation of TFIIH-associated nucleotide excision repair activity". Nat. Genet. 10 (2): 188–95. doi:10.1038/ng0695-188. hdl: 1765/54884 . PMID   7663514. S2CID   38325851.
• Maxon ME, Goodrich JA, Tjian R (1994). "Transcription factor IIE binds preferentially to RNA polymerase IIa and recruits TFIIH: a model for promoter clearance". Genes Dev. 8 (5): 515–24. doi: 10.1101/gad.8.5.515 . PMID   7926747.
• 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.
• Drapkin R, Reardon JT, Ansari A, Huang JC, Zawel L, Ahn K, Sancar A, Reinberg D (1994). "Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II". Nature. 368 (6473): 769–72. Bibcode:1994Natur.368..769D. doi:10.1038/368769a0. PMID   8152490. S2CID   4363484.
• van Vuuren AJ, Vermeulen W, Ma L, Weeda G, Appeldoorn E, Jaspers NG, van der Eb AJ, Bootsma D, Hoeijmakers JH, Humbert S (1994). "Correction of xeroderma pigmentosum repair defect by basal transcription factor BTF2 (TFIIH)". EMBO J. 13 (7): 1645–1653. doi:10.1002/j.1460-2075.1994.tb06428.x. PMC   394995 . PMID   8157004.
• Schaeffer L, Moncollin V, Roy R, Staub A, Mezzina M, Sarasin A, Weeda G, Hoeijmakers JH, Egly JM (1994). "The ERCC2/DNA repair protein is associated with the class II BTF2/TFIIH transcription factor". EMBO J. 13 (10): 2388–2392. doi:10.1002/j.1460-2075.1994.tb06522.x. PMC   395103 . PMID   8194528.
• Guzder SN, Sung P, Bailly V, Prakash L, Prakash S (1994). "RAD25 is a DNA helicase required for DNA repair and RNA polymerase II transcription". Nature. 369 (6481): 578–81. Bibcode:1994Natur.369..578G. doi:10.1038/369578a0. PMID   8202161. S2CID   4332757.
• Vermeulen W, Scott RJ, Rodgers S, Müller HJ, Cole J, Arlett CF, Kleijer WJ, Bootsma D, Hoeijmakers JH, Weeda G (1994). "Clinical heterogeneity within xeroderma pigmentosum associated with mutations in the DNA repair and transcription gene ERCC3". Am. J. Hum. Genet. 54 (2): 191–200. PMC   1918172 . PMID   8304337.
• Scott RJ, Itin P, Kleijer WJ, Kolb K, Arlett C, Muller H (1993). "Xeroderma pigmentosum-Cockayne syndrome complex in two patients: absence of skin tumors despite severe deficiency of DNA excision repair". J. Am. Acad. Dermatol. 29 (5 Pt 2): 883–9. doi:10.1016/0190-9622(93)70263-S. PMID   8408834.
• Blau J, Xiao H, McCracken S, O'Hare P, Greenblatt J, Bentley D (1996). "Three functional classes of transcriptional activation domain". Mol. Cell. Biol. 16 (5): 2044–2055. doi:10.1128/MCB.16.5.2044. PMC   231191 . PMID   8628270.
• Iyer N, Reagan MS, Wu KJ, Canagarajah B, Friedberg EC (1996). "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". Biochemistry. 35 (7): 2157–2167. doi:10.1021/bi9524124. PMID   8652557.
• Hwang JR, Moncollin V, Vermeulen W, Seroz T, van Vuuren H, Hoeijmakers JH, Egly JM (1996). "A 3' → 5' XPB helicase defect in repair/transcription factor TFIIH of xeroderma pigmentosum group B affects both DNA repair and transcription". J. Biol. Chem. 271 (27): 15898–904. doi: 10.1074/jbc.271.27.15898 . hdl: 1765/3098 . PMID   8663148.

External links

• GeneReviews/NIH/NCBI/UW entry on Xeroderma Pigmentosum
• XPBC-ERCC-3+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)