Defective Artemis causes mild telomere dysfunction

We observed significantly elevated frequencies of telomeric fusions in two primary fibroblast cell lines established from Artemis defective patients relative to the control cell line. The frequencies of telomeric fusions increased after exposure of Artemis defective cells to ionizing radiation. Furthermore, we observed increased incidence of DNA damage at telomeres in Artemis defective cells that underwent more than 32 population doublings using the TIF (Telomere dysfunction Induced Foci) assay. We have also inhibited the expression levels of DNA-PKcs in Artemis defective cell lines by either using synthetic inhibitor (IC86621) or RNAi and observed their greater sensitivity to telomere dysfunction relative to control cells.These results suggest that defective Artemis causes a mild telomere dysfunction phenotype in human cell lines.There is increasing evidence that the maintenance of telomeres, physical ends of chromosomes, and DNA damage response mechanisms are interlinked. The first observation of a telomere dysfunction phenotype in a DNA damage response defective environment was reported in the case of Ataxia telangiectasia (AT) cells. The telomere dysfunction phenotype in cells from AT patients or ATM (AT mutated) defective mice ranges from accelerated telomere shortening to end-to-end chromosome fusions and extra-chromosomal telomeric fragments [1,2]. Following the observation of telomere dysfunction associated with the ATM defect, a number of DNA damage response factors have been shown to affect telomere maintenance. Most notably, proteins involved in the repair of DNA double strand breaks (DSBs) either by Non-Homologous End Joining (NHEJ) or homologous recombination (HR) including Ku, DNA-PKcs, RAD54, RAD51D and BRCA1 if dysfunctional, will cause a severe telomere dysfunction phenotype [3-6]. So far, at least 17 DNA damage response proteins have been shown to affect telomere maintenance [7]. It is not yet clear as to why the interplay between telomere maintena