NUCLEOTIDE EXCISION-REPAIR SYNDROMES - MOLECULAR-BASIS AND CLINICAL SYMPTOMS

The phenotypic consequences of a nucleotide excision repair (NER) defe ct in man are apparent from three distinct inborn diseases characteriz ed by hypersensitivity of the skin to ultraviolet light and a remarkab le clinical and genetic heterogeneity. These are the prototype repair syndrome, xeroderma pigmentosum (XP) (seven genetic complementation gr oups, designated XP-A to XP-G), Cockayne's syndrome (two groups: CS-A and CS-B) and PIBIDS, a peculiar photosensitive form of the brittle ha ir disease trichothiodystrophy (TTD, at least two groups of which one equivalent to XP-D). To investigate the mechanism of NER and to resolv e the molecular defect in these NER deficiency diseases we have focuse d on the cloning and characterization of human DNA repair genes. One o f the genes that we cloned is ERCC3. It specifies a chromatin binding helicase. Transfection and microinjection experiments demonstrated tha t mutations in ERCC3 are responsible for XP complementation group B, a very rare form of XP that is simultaneously associated with Cockayne' s syndrome (CS). The ERCC3 protein was found to be part of a multiprot ein complex (TFIIH) required for transcription initiation of most stru ctural genes and for NER. This defines the additional, hitherto unknow n vital function of the gene. This ERCC3 gene and several other NER ge nes involved in transcription initiation will be discussed.