Abstract
Ku70/80 heterodimer is a central element in the nonhomologous end joining (NHEJ) DNA repair pathway, Ku80 playing a key role in regulating the multiple functions of Ku proteins. It has been found that the Ku80 protein located at telomeres is a major contributor to radiosensitivity in some telomerase positive human cancer cells. However, in ALT human osteosarcoma cells, the precise function in radiosensitivity and telomere maintenance is still unknown. The aim of this study was to investigate the effects of Ku80 depletion in the U2OS ALT cell line cell line. Suppression of Ku80 expression was performed using a vector-based shRNA and stable Ku80 knockdown in cells was verified by Western blotting. U2OS cells treated with shRNA-Ku80 showed lower radiobiological parameters (D0, Dq and SF2) in clonogenic assays. Furthermore, shRNA-Ku80 vector transfected cells displayed shortening of the telomere length and showed less expression of TRF2 protein. These results demonstrated that down-regulation of Ku80 can sensitize ALT cells U2OS to radiation, and this radiosensitization is related to telomere length shortening.
Highlights
Ku80 is one subunit of the Ku80/Ku70 heterodimer
Ku80 is a versatile regulatory protein that has been shown to play a crucial role in multiple nuclear processes such as DNA repair, telomere maintenance and apoptosis
In telomerase negative cancer cells, how does the Ku80 protein works without the association of hTERT? Here, we have demonstrated that in the telomerase negative cancer cells U2OS, decreased Ku80 expression exhibit significant telomere shortening
Summary
Ku80 is one subunit of the Ku80/Ku70 heterodimer. The crucial role of Ku80 in DNA damage was well known, especially the NHEJ pathway. When DNA is damaged, Ku heterodimer recruits DNA-PKcs to the DSB and activates its kinase function. This process stimulates DNA repair and the damage signal pathway, which may subsequently affect apoptosis and cell cycles. Previous studies demonstrated that mutation in Ku80 proteins prevent repair of telomere ends (Polotnianka et al, 1998) and these results reduced telomere lengthen and enhanced the radiosensitivity in many cell lines (Yang et al, 2008). The aim of this study was to investigate the relationship between radiosensitivity, telomere length and Ku80 protein in telomerase negative cancer cells
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