title: Hot topics in DNA repair: the molecular basis for different disease states caused by mutations in TFIIH and XPG.
abstract: Alterations in genes involved in nucleotide excision repair (NER) are associated with three genetic disorders, xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). The transcription and repair factor TFIIH is a central component of NER and mutations of its subunits are associated with all three diseases. A recent report provides a molecular basis for how mutations in the NER endonuclease XPG that affect the interaction of TFIIH might give rise to CS features. In cells of XP-G patients with a combined XP and CS phenotype, XPG fails to associate with TFIIH and as a consequence the CAK subunit dissociates from core TFIIH. A simplified, but general model of how various assembly and disassembly states of TFIIH can be invoked to explain different disease states is discussed. Accordingly, defects in specific enzymatic functions typically result in XP, dissociation of the CAK subunit from TFIIH is associated with XP/CS and a more generalized destabilization of TFIIH gives rise to TTD. While this classification provides a useful framework to understand how alterations in TFIIH correlate with disease states, it does not universally apply and relevant exception and alternative explanations are discussed.
authors: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11974-3400, USA. orlando@pharm.stonybrook.edu
authors: Orlando D
authors: OD
authors: Schärer
mesh_terms: D003057:Cockayne Syndrome / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D051758:Transcription Factor TFIIH / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D054463:Trichothiodystrophy Syndromes / Q000235:genetics*; D014983:Xeroderma Pigmentosum / Q000235:genetics*; D000099250:DNA Excision Repair Protein ERCC-5
chemical_list: D004268:DNA-Binding Proteins; D004720:Endonucleases; D009687:Nuclear Proteins; D051758:Transcription Factor TFIIH; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5