A 3'-]5'XPB HELICASE DEFECT IN REPAIR TRANSCRIPTION FACTOR TFIIH OF XERODERMA-PIGMENTOSUM GROUP-B AFFECTS BOTH DNA-REPAIR AND TRANSCRIPTION/

XPB is a subunit of the basal transcription factor TFIIH, which is als o involved in nucleotide excision repair (NER) and potentially in cell cycle regulation. A frameshift mutation in the 3'-end of the XPB gene is responsible for a concurrence of two disorders: xeroderma pigmento sum (XP) and Cockayne's syndrome (CS). We have isolated TFIIH from cel ls derived hom a patient (XP11BE) who carries this frameshift mutation (TFIIHmut) and from the mother of this patient (TFIIHwt) to determine the biochemical consequences of the mutation. Although identical in c omposition and stoichiometry to TFIIHwt, TFFIIHmut shows a reduced 3' --> 5' XPB helicase activity. A decrease in helicase and DNA-dependent ATPase activities was also observed with the mutated recombinant XPB protein. The XPB mutation causes a severe NER defect. In addition, we provide evidence for a decrease in basal transcription activity in vit ro. The latter defect may provide an explanation for many of the XP an d CS symptoms that are difficult to rationalize based solely on an NER defect. Thus, this work presents the first detailed analysis of a nat urally occurring mutation in a basal transcription factor and supports the concept that the combined XP/CS clinical entity is actually the r esult of a combined transcription/repair deficiency.