Ultraviolet-sensitive syndrome cells are defective in transcription-coupled repair of cyclobutane pyrimidine dimers.
Patients with ultraviolet-sensitive syndrome (UV(S)S) are sensitive to sunlight, but present neither developmental nor neurological deficiencies. Complementation studies with hereditary DNA repair syndromes show that UV(S)S is distinct from all known xeroderma pigmentosum (XP) and Cockayne syndrome (CS) groups. UV(S)S cells exhibit some characteristics typical of CS, including normal global genomic (GGR) repair of UV-photoproducts, poor clonal survival and defective recovery of RNA synthesis after UV exposure. Those observations have led us to suggest that UV(S)S cells, like those from CS, are defective in transcription-coupled repair (TCR) of cyclobutane pyrimidine dimers (CPD). We have now examined the repair of CPD in the transcribed and non-transcribed strands of the active dihydrofolate reductase (DHFR) and p53 genes, and of the silent alpha-fetoprotein (AFP) and mid-size neurofilament (NF-M) genes in normal human cells and in cells belonging to UV(S)S and CS complementation group B. Our results provide compelling evidence that the UV(S)S gene is essential for TCR of CPD and probably other bulky DNA lesions. As a possible distinction between UV(S)S and CS patients, we postulate that the UV(S)S gene may not be required for TCR of oxidative lesions. We have also found that repair of CPD in either DNA strand of the genomic fragments examined, occurs at a slower rate in TCR-deficient cells than in the non-transcribed strands in normal cells; we suggest that in the absence of TCR, global repair complexes have hindered access to lesions in genomic regions that extend beyond individual transcription units.
Spivak
Graciela
G
Department of Biological Sciences, Stanford University, Stanford, CA 94305-5020, USA. gspivak@stanford.edu
Itoh
Toshiki
T
Matsunaga
Tsukasa
T
Nikaido
Osamu
O
Hanawalt
Philip
P
Yamaizumi
Masaru
M
D002478:Cells, Cultured; D003057:Cockayne Syndrome / Q000235:genetics*; D004247:DNA / Q000528:radiation effects*; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics* / Q000528:radiation effects; D005347:Fibroblasts / Q000528:radiation effects; D016158:Genes, p53 / Q000502:physiology*; D006801:Humans; D016900:Neurofilament Proteins / Q000235:genetics; D011740:Pyrimidine Dimers / Q000235:genetics*; D012313:RNA / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D011836:Radiation Tolerance; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D014158:Transcription, Genetic; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics; D000509:alpha-Fetoproteins / Q000235:genetics*
D016900:Neurofilament Proteins; D011740:Pyrimidine Dimers; D000509:alpha-Fetoproteins; D012313:RNA; D004247:DNA; D013762:Tetrahydrofolate Dehydrogenase