ATM-deficient human fibroblast cells are resistant to low levels of DNA double-strand break induced apoptosis and subsequently undergo drug-induced premature senescence

Journal Article · Fri Jan 04 04:00:00 EST 2013 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2012.11.040· OSTI ID:22210377

Park, Jun; Jo, Yong Hwa; Cho, Chang Hoon; Choe, Wonchae; Kang, Insug; Baik, Hyung Hwan ^[1]; Yoon, Kyung-Sik ^[1]

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1. Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, 26 Kyunghee-daero, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of)

Highlights: Black-Right-Pointing-Pointer A-T cells were not hypersensitive to low levels of DNA DSBs. Black-Right-Pointing-Pointer A-T cells have enhanced Akt but defect in activation of p53 and apoptotic proteins. Black-Right-Pointing-Pointer A-T cells underwent premature senescence after DNA damage accumulated. Black-Right-Pointing-Pointer Chemotherapeutic effect in cancer therapy may be associated with premature senescence. -- 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-{beta}-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.

• OSTI ID: 22210377
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 1 Vol. 430; ISSN 0006-291X; ISSN BBRCA9
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
DNA
DNA REPAIR
DOXORUBICIN
FIBROBLASTS
INCUBATION
MORPHOLOGY
NEOPLASMS
PROTEINS
RADIOMIMETIC DRUGS
STRAND BREAKS
THERAPY