title: Hereditary ataxia SCAN1 cells are defective for the repair of transcription-dependent topoisomerase I cleavage complexes.
abstract: 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.
authors.affiliation: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ze-Hong
authors.initials: ZH
authors.lastname: Miao
authors.forename: Keli
authors.initials: K
authors.lastname: Agama
authors.forename: Olivier
authors.initials: O
authors.lastname: Sordet
authors.forename: Lawrence
authors.initials: L
authors.lastname: Povirk
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Kohn
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: 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
chemical_list: D016590:Aphidicolin; D010727:Phosphoric Diester Hydrolases; C122147:tyrosyl-DNA phosphodiesterase; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin