ATM-deficient human fibroblast cells are resistant to low levels of DNA double-strand break induced apoptosis and subsequently undergo drug-induced premature senescence |
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| Authors: | Jun Park Yong Hwa Jo Chang Hoon Cho Wonchae Choe Insug Kang Hyung Hwan Baik Kyung-Sik Yoon |
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| Institution: | 3. From the Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung City 40201, Taiwan,;4. School of Medicine, Graduate Institute of Biomedical Sciences, Chang-Gung University, Taoyuan 33302, Taiwan,;5. Clinical Laboratory, Chung Shan Medical University Hospital, Taichung City 40201, Taiwan;1. Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Královopolská 135, 612 65 Brno, Czech Republic;2. Core Facility–Proteomics, Central European Institute of Technology, Masaryk University, Kamenice 753/5, Brno, Czech Republic;3. Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel;4. Medical Research Council (MRC) Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, United Kingdom;1. Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan;2. Center for Parkinson’s Disease, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan;3. Chang Gung University College of Medicine, Kaohsiung, Taiwan;1. Center for Uterine Cancer, Research Institute and Hospital, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea;2. Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si, Gyevonggi-do 410-769, Republic of Korea |
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| Abstract: | DNA DSBs are induced by IR or radiomimetic drugs such as doxorubicin. It has been indicated that cells from ataxia-telangiectasia patients are highly sensitive to radiation due to defects in DNA repair, but whether they have impairment in apoptosis has not been fully elucidated. A-T cells showed increased sensitivity to high levels of DNA damage, however, they were more resistant to low doses. Normal cells treated with combination of KU55933, a specific ATM kinase inhibitor, and doxorubicin showed increased resistance as they do in a similar manner to A-T cells. A-T cells have higher viability but more DNA breaks, in addition, the activations of p53 and apoptotic proteins (Bax and caspase-3) were deficient, but Akt expression was enhanced. A-T cells subsequently underwent premature senescence after treatment with a low dose of doxorubicin, which was confirmed by G2 accumulation, senescent morphology, and SA-β-gal positive until 15 days repair incubation. Finally, A-T cells are radio-resistant at low doses due to its defectiveness in detecting DNA damage and apoptosis, but the accumulation of DNA damage leads cells to premature senescence. |
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