Hereditary ataxia SCAN1 cells are defective for the repair of transcription-dependent topoisomerase I cleavage complexes.
Hereditary spinocerebellar ataxia with axonal neuropathy (SCAN1) is caused by an inactivating mutation (H493R) in the enzyme tyrosyl-DNA phosphodiesterase (Tdp1), which removes blocked 3'-termini at DNA strand breaks. Using SCAN1 cells treated with the specific topoisomerase I (Top1) inhibitor camptothecin, we find enhanced levels of Top1 cleavage complexes (Top1cc) and defective reversal of Top1cc in SCAN1 Tdp1-deficient cells, indicating a direct involvement of Tdp1 in the repair of Top1cc. Because the defective removal of Top1cc and the hypersensitivity of SCAN1 cells to camptothecin are not affected by aphidicolin, we propose that Tdp1 is involved in the repair of Top1cc associated with transcription damage in SCAN1 cells.
Miao
Ze-Hong
ZH
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Agama
Keli
K
Sordet
Olivier
O
Povirk
Lawrence
L
Kohn
Kurt W
KW
Pommier
Yves
Y
D016590:Aphidicolin / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology*; D002460:Cell Line; D004260:DNA Repair; D004261:DNA Replication / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D006801:Humans; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D016590:Aphidicolin; D010727:Phosphoric Diester Hydrolases; C122147:tyrosyl-DNA phosphodiesterase; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin