The cancer-free phenotype in trichothiodystrophy is unrelated to its repair defect

The DNA repair-deficient genetic disorders xeroderma pigmentosum (XP) and t richothiodystrophy (TTD) can both result from mutations in the XPD gene, th e sites of the mutations differing between the two disorders. The hallmarks of XP are multiple pigmentation changes in the skin and a greatly elevated frequency of skin cancers, characteristics that are not seen in TTD, XP-D and most TTD patients have reduced levels of DNA repair, but some recent re ports have suggested that the repair deficiencies in TTD cells are milder t han in XP-D cells. We reported recently that inhibition of intracellular ad hesion molecule-1 (ICAM-1) expression by UVB irradiation was similar in nor mal and TTD cells but increased in XP-D cells, suggesting a correlation bet ween ICAM-1 inhibition and cancer proneness. In the first part of the curre nt work, we have extended these studies and found several other examples, i ncluding XP-G and Cockayne syndrome cells, in which increased ICAM-1 inhibi tion correlated with cancer proneness. However, we also discovered that a s ubset of TTD cells, in which arg112 in the NH2-terminal region of the XPD p rotein is mutated to histidine, had an ICAM-1 response similar to that of X P-D cells. In the second part of the work, we have shown that TTD cells wit h this specific NH2-terminal mutation are more sensitive to UV irradiation than other TTDs, most of which are mutated in the COOH-terminal region, and are indistinguishable from XP-D cells in cell killing, incision breaks, an d repair of cyclobutane pyrimidine dimers. Because the clinical phenotypes of these patients do not obviously differ from those of TTDs with mutations at other sites, we conclude that the lack of skin abnormalities in TTD is independent of the defective cellular responses to UV. It is likely to resu lt from a transcriptional defect, which prevents the skin abnormalities fro m being expressed.