title: Mutations in Cullin 4B result in a human syndrome associated with increased camptothecin-induced topoisomerase I-dependent DNA breaks.
abstract: CUL4A and B encode subunits of E3-ubiquitin ligases implicated in diverse processes including nucleotide excision repair, regulating gene expression and controlling DNA replication fork licensing. But, the functional distinction between CUL4A and CUL4B, if any, is unclear. Recently, mutations in CUL4B were identified in humans associated with mental retardation, relative macrocephaly, tremor and a peripheral neuropathy. Cells from these patients offer a unique system to help define at the molecular level the consequences of defective CUL4B specifically. We show that these patient-derived cells exhibit sensitivity to camptothecin (CPT), impaired CPT-induced topoisomerase I (Topo I) degradation and ubiquitination, thereby suggesting Topo I to be a novel Cul4-dependent substrate. Consistent with this, we also find that these cells exhibit increased levels of CPT-induced DNA breaks. Furthermore, over-expression of known CUL4-dependent substrates including Cdt1 and p21 appear to be a feature of these patient-derived cells. Collectively, our findings highlight the interplay between CUL4A and CUL4B and provide insight into the pathogenesis of CUL4B-deficiency in humans.
authors.affiliation: Human DNA Damage Response Disorders Group, University of Sussex, Brighton, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kerzendorfer
authors.forename: Annabel
authors.initials: A
authors.lastname: Whibley
authors.forename: Gillian
authors.initials: G
authors.lastname: Carpenter
authors.forename: Emily
authors.initials: E
authors.lastname: Outwin
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Chiang
authors.forename: Gillian
authors.initials: G
authors.lastname: Turner
authors.forename: Charles
authors.initials: C
authors.lastname: Schwartz
authors.forename: Sherif
authors.initials: S
authors.lastname: El-Khamisy
authors.forename: F Lucy
authors.initials: FL
authors.lastname: Raymond
authors.forename: Mark
authors.initials: M
authors.lastname: O'Driscoll
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D002166:Camptothecin / Q000494:pharmacology*; D002460:Cell Line; D044842:Cullin Proteins / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D013577:Syndrome; D054875:Ubiquitination
chemical_list: C114234:CUL4A protein, human; C517832:CUL4B protein, human; D044842:Cullin Proteins; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin