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Cyclobutane Pyrimidine Dimers are the Main Mutagenic DNA Photoproducts in DNA Repair-deficient Trichothiodystrophy Cells¹

Laboratory of Molecular Genetics, UPR 42 Centre National de la Recherche Scientifique IFC1, Institute de Recherches sur le Cancer, BP8-94801 Villejuif, France

We have used the replicating shuttle vector pR2 to determine the role of ultraviolet C (UVC)-induced cyclobutane pyrimidine dimers (CPDs) and nondimer photoproducts in mutagenesis in human trichothiodystrophy (TTD) cells and in their repair-proficient counterparts obtained after complementation with the wild-type XPD/ERCC2 repair gene (TTD + ERCC2 cells). Before transfection in human cells, the UVC-irradiated vector DNA was treated with Anacystis nidulans photolyase [photoreactivation (PR) procedure] that selectively removed CPDs, leaving nondimer photoproducts intact. The mutant frequency of the UV-irradiated pR2 plasmid treated by PR was similar after replication in TTD or in TTD + ERCC2 cells. This result indicates that TTD cells were able to repair nondimer photoproducts as efficiently as TTD cells complemented with the wild-type repair gene and that in TTD cells, CPDs were the major photoproducts generating an increased mutant frequency after UVC irradiation. Sequence analysis of >300 mutant plasmids indicated that PR of the DNA increased the relative level of tandem mutations and decreased the relative level of multiple mutations in TTD cells. In both cell lines, we observed that CPDs mostly led to GC-AT transitions; whereas only nondimer photoproducts were responsible for the induction of GC-TA transversions in TTD and TTD + ERCC2 cells.

¹ Supported by grants from the Fondation de France (Paris, France), the Ligue Nationale contre le Cancer (Paris, France), and the Association Française contre les Myopathies (Paris, France). C. M. held a fellowship from the Centre National de la Recherche Scientifique (Paris, France).

² To whom requests for reprints should be addressed. Phone: 33-1-49-58-34-20; Fax: 33-1-49-58-34-43.

Received 7/ 2/97. Accepted 10/29/97.

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