Related Experiment Videos
The ATM protein is required for sustained activation of NF-kappaB following DNA damage
B Piret1, S Schoonbroodt, J Piette
1Laboratory of Fundamental Virology and Immunology, University of Liège, CHU, Belgium.
Abstract:
Cells lacking an intact ATM gene are hypersensitive to ionizing radiation and show multiple defects in the cell cycle-coupled checkpoints. DNA damage usually triggers cell cycle arrest through, among other things, the activation of p53. Another DNA-damage responsive factor is NF-kappaB. It is activated by various stress situations, including oxidative stress, and by DNA-damaging compounds such as topoisomerase poisons. We found that cells from Ataxia Telangiectasia patients exhibit a defect in NF-kappaB activation in response to treatment with camptothecin, a topoisomerase I poison. In AT cells, this activation is shortened or suppressed, compared to that observed in normal cells. Ectopic expression of the ATM protein in AT cells increases the activation of NF-kappaB in response to camptothecin. MO59J glioblastoma cells that do not express the DNA-PK catalytic subunit respond normally to camptothecin. These results support the hypothesis that NF-kappaB is a DNA damage-responsive transcription factor and that its activation pathway by DNA damage shares some components with the one leading to p53 activation.
Insights
Cells with ATM gene defects show impaired NF-kappaB activation after DNA damage. Restoring ATM protein function in Ataxia Telangiectasia (AT) cells normalizes this response, suggesting ATM
Area of Science:
- Molecular Biology
- Cellular Biology
- Genetics
Background:
- Cells lacking a functional ATM gene are sensitive to DNA damage and have cell cycle checkpoint defects.
- Nuclear factor-kappa B (NF-kappaB) is activated by stress and DNA-damaging agents.
- p53 is a key factor activated by DNA damage, leading to cell cycle arrest.
Purpose of the Study:
- To investigate the role of the ATM gene in the DNA damage-induced activation of NF-kappaB.
- To determine if NF-kappaB is a DNA damage-responsive transcription factor.
Main Methods:
- Comparison of NF-kappaB activation in Ataxia Telangiectasia (AT) cells versus normal cells following camptothecin treatment.
- Assessment of NF-kappaB activation in AT cells with ectopic ATM protein expression.
- Analysis of camptothecin response in DNA-PK catalytic subunit-deficient glioblastoma cells.
Main Results:
- AT cells exhibit defective and suppressed NF-kappaB activation upon camptothecin treatment compared to normal cells.
- Ectopic ATM expression in AT cells restores normal NF-kappaB activation in response to camptothecin.
- DNA-PK deficient cells show normal NF-kappaB activation, indicating ATM's specific role.
Conclusions:
- NF-kappaB is a DNA damage-responsive transcription factor.
- The activation pathway of NF-kappaB by DNA damage shares components with the p53 activation pathway.
- ATM protein plays a crucial role in the DNA damage-induced activation of NF-kappaB.