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Radiation down-regulates replication origin activity throughout the S phase in mammalian cells
J M Larner1, H Lee, R D Little
1Department of Therapeutic Radiology and Oncology, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA, jlh2d@virginia.edu
Nucleic Acids Research
|January 16, 1999
Summary
Ionizing radiation inhibits DNA replication by down-regulating origin initiation in human cells. This DNA damage-sensing pathway is impaired in ataxia telangiectasia, affecting DNA repair.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Mammalian cells inhibit DNA replication post-ionizing radiation to repair damage.
- The S phase damage-sensing (SDS) pathway primarily affects cells near S phase entry.
- Previous studies indicated minimal impact on ongoing DNA replication within S phase.
Purpose of the Study:
- To investigate if ionizing radiation inhibits replication origins activated within S phase.
- To determine the role of the SDS pathway in regulating replication origins.
- To confirm the absence of the SDS pathway in ataxia telangiectasia.
Main Methods:
- Two-dimensional gel replicon mapping was employed.
- Analysis was conducted on human cells with an intact SDS pathway.
- Replication origin activity was assessed in cells from ataxia telangiectasia patients.
Main Results:
- Cells with an intact SDS pathway completely inhibited initiation at early- and late-firing rDNA origins.
- Initiation at mid- and late-firing rDNA origins remained unaffected in ataxia telangiectasia cells.
- This confirms the deficiency of the SDS pathway in ataxia telangiectasia.
Conclusions:
- Ionizing radiation actively down-regulates replication origin initiation via the SDS pathway.
- The SDS pathway is crucial for preventing replication from damaged DNA.
- Ataxia telangiectasia patients exhibit a defective SDS pathway, impacting DNA replication control.