Journal Article

Mutations in <i>Cullin 4B</i> result in a human syndrome associated with increased camptothecin-induced topoisomerase I-dependent DNA breaks

Claudia Kerzendorfer, Annabel Whibley, Gillian Carpenter, Emily Outwin, Shih-Chieh Chiang, Gillian Turner, Charles Schwartz, Sherif El-Khamisy, F. Lucy Raymond and Mark O'Driscoll

in Human Molecular Genetics

Volume 19, issue 7, pages 1324-1334
Published in print April 2010 | ISSN: 0964-6906
Published online January 2010 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq008
Mutations in Cullin 4B result in a human syndrome associated with increased camptothecin-induced topoisomerase I-dependent DNA breaks

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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.

Journal Article.  6195 words.  Illustrated.

Subjects: Genetics and Genomics

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