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A Roberts syndrome individual with differential genotoxin sensitivity and a DNA damage response defect
journal contribution
posted on 2019-04-01, 00:00 authored by Michael J McKay, Jeffrey CraigJeffrey Craig, Paul Kalitsis, Sergei Kozlov, Sandra Verschoor, Phillip Chen, Pavel Lobachevsky, Raja Vasireddy, Yuqian Yan, Jacinta Ryan, George McGillivray, Ravi Savarirayan, Martin F Lavin, Robert G Ramsay, Huiling XuPURPOSE: Roberts syndrome (RBS) is a rare, recessively transmitted developmental disorder characterized by growth retardation, craniofacial abnormalities, and truncation of limbs. All affected individuals to date have mutations in the ESCO2 (establishment of cohesion 2) gene, a key regulator of the cohesin complex, which is involved in sister chromatid cohesion and DNA double-strand break (DSB) repair. Here we characterize DNA damage responses (DDRs) for the first time in an RBS-affected family. METHODS AND MATERIALS: Lymphoblastoid cell lines were established from an RBS family, including the proband and parents carrying ESCO2 mutations. Various DDR assays were performed on these cells, including cell survival, chromosome break, and apoptosis assays; checkpoint activation indicators; and measures of DNA breakage and repair. RESULTS: Cells derived from the RBS-affected individual showed sensitivity to ionizing radiation (IR) and mitomycin C-induced DNA damage. In this ESCO2 compound heterozygote, other DDRs were also defective, including enhanced IR-induced clastogenicity and apoptosis; increased DNA DSB induction; and a reduced capacity for repairing IR-induced DNA DSBs, as measured by γ-H2AX foci and the comet assay. CONCLUSIONS: In addition to its developmental features, RBS can be, like ataxia telangiectasia, considered a DDR-defective syndrome, which contributes to its cellular, molecular, and clinical phenotype.
History
Journal
International journal of radiation oncology, biology, physicsVolume
103Issue
5Pagination
1194 - 1202Publisher
ElsevierLocation
Amsterdam, The NetherlandsPublisher DOI
eISSN
1879-355XLanguage
engPublication classification
C Journal article; C1 Refereed article in a scholarly journalCopyright notice
2018, Elsevier Inc.Usage metrics
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