Abnormal regulation of DNA replication and increased lethality in ataxia telangiectasia cells exposed to carcinogenic agents
The effect of different carcinogenic agents on the rate of semiconservative DNA replication in normal and ataxia telangiectasis (AT) cells was investigated. The rate of DNA synthesis in all AT cell strains tested was depressed to a significantly lesser extent than in normal cells after exposure to X-rays under oxia or hypoxia or to bleomycin, agents to which AT cells are hypersensitive. In contrast, inhibition of DNA replication in normal human and AT cells was similar after treatment with some DNA-methylating agents or mitomycin C. Colony-forming ability of AT cells treated with these agents was not different from normal cells. Treatment with 4-nitroquinoline 1-oxide elicited a variable response in both AT and normal cell strains. In some strains, including those shown to be hypersensitive to the drug by other workers, the inhibition of DNA synthesis was more pronounced than in other cell strains, but no significant difference between AT and normal cells could be detected. The rejoining of DNA strand breaks induced by X-rays, measured by DNA elution techniques, occurred within l2 hr after treatment and could not be correlated with the difference in DNA synthesis inhibition in AT and normal cells. After low doses of X-rays, AT cells rejoined single-strand breaks slightly more slowly than did normal cells. The rate of DNA replication in X-irradiation AT and normal cells was not affected by nicotinamide, an inhibitor of poly(adenosine diphosphate ribose) synthesis. These data indicate that the diminished inhibition of DNA replication in carcinogen-treated AT cells (a) is a general characteristic of all AT cell strains, (b) correlates with AT cellular hypersensitivity, (c) is not directly caused by the bulk of the DNA strand breaks produced by carcinogenic agents, and (d) is not based on differences in the induction of poly(adenosine diphosphate ribose) synthesis between X-irradiated AT and normal cells.
- Research Organization:
- Department of Cell Biology and Genetics, Erasmus University Rotterdam, The Netherlands
- OSTI ID:
- 5448870
- Journal Information:
- Cancer Res.; (United States), Vol. 42:1
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
59 BASIC BIOLOGICAL SCIENCES
CELL CULTURES
RADIOSENSITIVITY
DNA REPLICATION
BIOLOGICAL RADIATION EFFECTS
NICOTINAMIDE
RADIOSENSITIVITY EFFECTS
QUINOLINES
ANOXIA
BIOLOGICAL REPAIR
BLEOMYCIN
DNA
PATHOLOGY
STRAND BREAKS
TELANGIECTASIS
X RADIATION
AMIDES
ANTI-INFECTIVE AGENTS
ANTIBIOTICS
ANTIMITOTIC DRUGS
ANTINEOPLASTIC DRUGS
AZINES
BIOLOGICAL EFFECTS
BIOLOGICAL RECOVERY
DISEASES
DRUGS
ELECTROMAGNETIC RADIATION
HETEROCYCLIC COMPOUNDS
IONIZING RADIATIONS
NUCLEIC ACID REPLICATION
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PYRIDINES
RADIATION EFFECTS
RADIATIONS
RECOVERY
REPAIR
SKIN DISEASES
VASCULAR DISEASES
VITAMIN B GROUP
VITAMINS
560121* - Radiation Effects on Cells- External Source- (-1987)
550900 - Pathology
550200 - Biochemistry