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Title: A Roberts Syndrome individual with differential genotoxin sensitivity and a DNA damage response defect.
Austin Authors: McKay, Michael J;Craig, Jeffery;Kalitsis, Paul;Kozlov, Sergei;Verschoor, Sandra;Chen, Phillip;Lobachevsky, Pavel;Vasireddy, Raja;Yan, Yuqian;Ryan, Jacinta;McGillivray, George;Savarirayan, Ravi;Lavin, Martin F;Ramsay, Robert G;Xu, Huiling
Affiliation: Clinical Pathology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
School of Medicine, Flinders University, Adelaide, South Australia 5001, Australia
Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia
University of Queensland Centre for Clinical Research, Royal Brisbane & Women's Hospital Campus, Herston, Queensland 4029, Australia
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria 3052, Australia
Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Latrobe University, Plenty Road, Bundoora, Victoria 3086, Australia
Austin Health, Heidelberg, Victoria, Australia
Issue Date: 30-Nov-2018
Date: 2018-11-30
Publication information: International journal of radiation oncology, biology, physics 2018; online first: 30 November
Abstract: 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 a RBS-affected family. Lymphoblastoid cell lines (LCLs) were established from an RBS family, including the proband, and parents carrying ESCO2 mutations. Various DDR assays were performed on these cells, including clonogenic, chromosome break and apoptosis assays, checkpoint activation indicators and measures of DNA breakage and repair. Cells derived from the RBS-affected individual showed sensitivity to ionizing radiation (IR) and Mitomycin C (MMC) -induced DNA damage. In this ESCO2 compound heterozygote, other DNA damage responses 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. in addition to its developmental features, RBS can be, like ataxia telangiectasia, considered a DNA damage response-defective syndrome, which contributes to its cellular, molecular and clinical phenotype.
DOI: 10.1016/j.ijrobp.2018.11.047
Journal: International journal of radiation oncology, biology, physics
PubMed URL: 30508616
Type: Journal Article
Appears in Collections:Journal articles

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