Common pathways for ultraviolet skin carcinogenesis in the repair and replication defective groups of xeroderma pigmentosum

The human disease xeroderma pigmentosum (XP) involves DNA repair and replic ation deficiencies that predispose homozygous individuals to a 1000-fold in crease in nonmelanoma and melanoma skin cancers. Two major forms of WP ale known with different biochemical defects: one form lacks nucleotide excisio n repair (NER); the other lacks the capacity to replicate damaged DNA. Sinc e the clinical symptoms of both kinds of patients are almost the same, the different cellular defects must be reconciled with common clinical outcomes . An additional question among the NER defective patients is how to reconci le widely different skin and central nervous system symptoms with mutations in the same biochemical pathway. SP involves seven genes of the NER system (XPA through G). The XPA gene codes for a protein that is central to NER a nd binds to a variety of UV light and chemical damage to DNA. It also acts as a nucleation center for other repair proteins to attach and carry out ex cision and replacement synthesis. Mutations in XPA that are within the DNA binding site produce more severe CNS disorders, than mutations in the C-ter minal region of the protein that interacts with the TFIIH complex. In contr ast, mutations in two members of the TFIIH complex, the XPB and XPD genes a re generally very severe with both skin and CNS disorders. Missense mutatio ns within the helicase regions of these genes are associated with DNA repai r deficiencies and XPD: mutations elsewhere in these genes are correlated w ith symptoms of XP and Cockayne syndrome and trichothiodystrophy. This rais es the question whether the CNS disorders of XPA, XPB, and XPD patients are similar, or whether a careful clinical evaluation might reveal different m echanisms of development. The XP variant lacks the capacity to replicate da maged DNA due to mutations in hRad30, a damage-specific polymerase eta. The phenotype of XP variant cells becomes unstable and the cells become much m ore UV-sensitive when they are transformed by methods that inactivate p53. On a p53 negative background, the induction of recombination between sister chromatids occurs much more extensively than in normal cells, and we have evidence that DNA double strand breaks which trigger an apoptotic pathway i nvolving caspase-3 are involved. The pathway for UV carcinogenesis may be t he same for all XP patients if the ultimate cause of genomic instability is an increase in replication of damaged DNA by the error-prone polymerase ze ta. The presence of unrepaired damage in the NER defective groups of XP wou ld present more substrate for the error-prone system leading to increased m utation rates. The absence of pol eta would require cells to use the error- prone pol zeta pathway; also increasing mutation rates from UV damage. A co mmon pathway for increased mutagenesis therefore underlies both forms of XP . (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.