XPB

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.

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

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

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,
• CDK7,
• ERCC2,
• GTF2H1,
• GTF2H2,
• GTF2H4,
• GTF2H5,
• P53,
• PSMC5, and
• XPC.

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.

References

References

1. (April 2006). "Conserved XPB Core Structure and Motifs for DNA Unwinding: Implications for Pathway Selection of Transcription or Excision Repair". Molecular Cell.
2. (2006). "Phenotypic heterogeneity in the XPB DNA helicase gene (ERCC3): xeroderma pigmentosum without and with Cockayne syndrome". Hum. Mutat..
3. (2009). "An Xpb mouse model for combined xeroderma pigmentosum and cockayne syndrome reveals progeroid features upon further attenuation of DNA repair". Mol. Cell. Biol..
4. (May 1996). "The XPB and XPD DNA helicases are components of the p53-mediated apoptosis pathway". Genes Dev.
5. (January 1999). "The BCR-ABL oncoprotein potentially interacts with the xeroderma pigmentosum group B protein". Proc. Natl. Acad. Sci. U.S.A..
6. (December 1995). "Molecular cloning of CDK7-associated human MAT1, a cyclin-dependent kinase-activating kinase (CAK) assembly factor". Cancer Res..
7. (July 2004). "A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A". Nat. Genet..
8. (March 1997). "Cloning and characterization of p52, the fifth subunit of the core of the transcription/DNA repair factor TFIIH". EMBO J..
9. (April 1994). "Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II". Nature.
10. (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.
11. (June 1995). "p53 modulation of TFIIH-associated nucleotide excision repair activity". Nat. Genet..
12. (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..
13. (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..
14. (2020). "A Glucose-Triptolide Conjugate Selectively Targets Cancer Cells under Hypoxia". iScience.