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Altered G1 checkpoint control determines adaptive survival responses to ionizing radiation
D A Boothman1, M Meyers, E Odegaard
1Department of Human Oncology, University of Wisconsin-Madison 53792, USA. boothman@vms2.macc.wisc.edu
Mutation Research
|November 4, 1996
Summary
Certain human cells exhibit adaptive survival responses (ASRs) to radiation after low-dose priming, showing enhanced radioresistance. This involves specific cell cycle proteins, suggesting a role in DNA repair and adaptation.
Area of Science:
- Cell Biology
- Radiobiology
- Molecular Oncology
Background:
- Adaptive survival responses (ASRs) involve increased cellular resistance to cytotoxic agents following prior low-dose exposures.
- Understanding the molecular mechanisms underlying ASRs is crucial for predicting cellular responses to genotoxic stress.
Purpose of the Study:
- To investigate the phenomenon of adaptive survival responses (ASRs) in various human cell types following ionizing radiation exposure.
- To identify molecular markers and pathways associated with ASRs in radioresistant human cells.
Main Methods:
- Priming of human normal, cancer-prone, and neoplastic cells with repeated low doses of X-rays, followed by a high-dose challenge.
- Assessment of cell survival, mRNA and protein expression (cyclins A, D1, PCNA), and cell cycle progression.
- Inhibition studies using cycloheximide and actinomycin D to probe the role of protein synthesis in ASRs.
Main Results:
- U1-Mel and HEp-2 neoplastic cells exhibited significant transient survival enhancement after low-dose X-ray priming.
- ASRs in these cells were dependent on protein synthesis and associated with increased cyclin A mRNA and protein, and constitutively elevated cyclin D1 and PCNA.
- Primed U1-Mel cells showed accelerated entry into S-phase, indicating altered cell cycle regulation; these responses were specific to certain cell lines.
Conclusions:
- ASRs in specific human cells are linked to progression through the G1 phase (A point), facilitating DNA repair and radioresistance.
- Constitutively high levels of PCNA and cyclin D1, along with inducible cyclin A, are correlated with ASRs.
- A protein complex involving cyclin D1, PCNA, and potentially cyclin A may regulate cell cycle progression and DNA repair, mediating ASRs in human cells.