title: Mutant Cockayne syndrome group B protein inhibits repair of DNA topoisomerase I-DNA covalent complex.
abstract: Two UV-sensitive syndrome patients who have mild photosensitivity without detectable somatic abnormalities lack detectable Cockayne syndrome group B (CSB) protein because of a homozygous null mutation in the CSB gene. In contrast, mutant CSB proteins are produced in CS-B patients with the severe somatic abnormalities of Cockayne syndrome and photosensitivity. It is known that the piggyBac transposable element derived 3 is integrated within the CSB intron 5, and that CSB-piggyBac transposable element derived 3 fusion (CPFP) mRNA is produced by alternative splicing. We found that CPFP or truncated CSB protein derived from CPFP mRNA was stably produced in CS-B patients, and that wild-type CSB, CPFP, and truncated CSB protein interacted with DNA topoisomerase I. We also found that CPFP inhibited repair of a camptothecin-induced topoisomerase I-DNA covalent complex. The inhibition was suppressed by the presence of wild-type CSB, consistent with the autosomal recessive inheritance of Cockayne syndrome. These results suggested that reduced repair of a DNA topoisomerase I-DNA covalent complex because of truncated CSB proteins is involved in the pathogenesis of CS-B.
authors.affiliation: Human Cell Biology Group, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Horibata
authors.forename: Masafumi
authors.initials: M
authors.lastname: Saijo
authors.forename: Mui N
authors.initials: MN
authors.lastname: Bay
authors.forename: Li
authors.initials: L
authors.lastname: Lan
authors.forename: Isao
authors.initials: I
authors.lastname: Kuraoka
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Brooks
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Honma
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
authors.forename: Akira
authors.initials: A
authors.lastname: Yasui
authors.forename: Kiyoji
authors.initials: K
authors.lastname: Tanaka
mesh_terms: D002460:Cell Line; D002461:Cell Line, Transformed; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000502:physiology*; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D007438:Introns; D050505:Mutant Proteins / Q000235:genetics*; D009154:Mutation; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger / Q000235:genetics; D014162:Transfection; D014466:Ultraviolet Rays
chemical_list: D050505:Mutant Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger; D004247:DNA; C513075:Ercc6 protein, mouse; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D045643:DNA Repair Enzymes