@article{b644bb47c76244fc888f70b248541dff,
title = "Human nucleotide excision repair syndromes: Molecular clues to unexpected intricacies",
author = "Hoeijmakers, \{J. H.J.\}",
note = "Funding Information: The selective association of BTF2 with the peculiar forms of XP and the dual role of this complex in repair and transcription make it tempting to link the unexpected TTD and CS features with the additional transcription-related function of the NER genes involved. Indeed, it would be highly unlikely that all mutations in the three subunits of this bifunctional complex would affect only the repair function, and leave the inherent transcriptional role intact. This interpretation is supported by the phenotype of a Drosophila ERCC3 mutant. This mutant called haywire displays UV sensitivity, central nervous system abnormalities and impaired sexual development, as found in XP-B [5 11. Spermatogenesis in Drosophila is very sensitive to the level of B2 tubulin [78]. Mutations in the Drosophila ERCC3 gene seem to affect B tubulin expression, causing male sterility [51]. It is, therefore, likely that expression of this gene in Drosophila (and by inference possibly in man) is particularly sensitive to the level of transcription and thereby to subtle mutations in BTFZ. This could explain the immature sexual development found in TTD and CS. Expression of the myelin basic protein is known to be critically dependent on transcription. Reduced transcription of this gene has been demonstrated to cause neurological abnormalities in the mouse [79]. Thus, the characteristic neurodysmyelination of CS and TTD [80, 8 l] may also relate to suboptimal transcription of this or other genes involved in myelin sheet formation. Similarly, reduced transcription of genes encoding the class of ultrahigh sulphur proteins of the hairshaft may account for the observed reduced cysteine content in the brittle hair of TTD patients [82]. A comparable explanation is proposed for the poor enamelation of teeth in CS and TTD [13, 831. The skin abnormalities typical of TTD often involve ichthyosis. Various classes of ichthyoses show abnormalities in the production of filaggrin [84]. Thus, mutations in BTF2 which subtly disturb its transcription function may affect a specific subset of genes whose functioning critically depends on the level or fine-tuning of transcription. Recent studies indicate that the requirement for basal transcription factors may vary from promoter to promoter depending on the sequence around the initiation site, the topological state of the DNA and the local chromatin structure [85-871. These mechanisms can readily explain the pronounced clinical heterogeneity within families.",
year = "1994",
doi = "10.1016/0959-8049(94)00381-E",
language = "English",
volume = "30",
pages = "1912--1921",
journal = "European Journal of Cancer",
issn = "0959-8049",
publisher = "Elsevier Ltd.",
number = "13",
}