Inhibition of DNA excision repair in human cells by Arabinofuranosyl cytosine: effect on normal and xeroderma pigmentosum cells
The antineoplastic agent arabinofuranosyl cytosine (ara-C) produces an inhibition of the pyrimidine dimer excision system of human DNA repair. Alkaline sucrose gradient analysis of DNA from normal human skin fibroblasts exposed to 20 J/m/sup 2/ of ultraviolet radiation (254 nm) shows an accumulation of DNA single-strand breaks when DNA repair is attempted in the presence of 10 ..mu..M ara-C. Cells from complementaion groups of xeroderma pigmentosum that are defective in early steps of excision repair show reduced numbers of DNA single strand breaks/10/sup 8/ daltons when compared with normal cells. Cesium chloride gradient analysis of radioactive precurser uptake during repair replication indicates that ara-C causes a 6 to 56% reduction in the number of nucleotide bases inserted into the DNA at concentrations of 1 and 10 ..mu..M, respectively. These concentrations result in the substitution for deoxycytidine (dCyd) by ara-C of 40 and 100%, respectively, in repaired regions. Repair inhibition is reversed by 50% upon removal of ara-C and by > 95% with the addition of 100 ..mu..M dCyd. Chromatography of digested DNA shows that incorporated ara-C is not removed during dCyd reversal, suggesting that ara-C incorporation per se does not play a significant role in the inhibition of repair synthesis. The repair inhibition observed here is dependent on 2 mM hydroxyurea, presumably due to reduction in the intracellular pool of dCyd. The overall results suggest the possibility that ara-C is a weak competitive inhibitor of DNA polymerases associated with ultraviolet-induced excision repair.
- Research Organization:
- Oak Ridge National Lab., TN
- OSTI ID:
- 5415215
- Journal Information:
- Mol. Pharmacol.; (United States), Vol. 15
- Country of Publication:
- United States
- Language:
- English
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ANTINEOPLASTIC DRUGS
PHARMACOLOGY
BIOLOGICAL REPAIR
INHIBITION
BIOCHEMISTRY
BIOLOGICAL RADIATION EFFECTS
DIMERS
DNA
FIBROBLASTS
MAN
POLYMERASES
PYRIMIDINES
STRAND BREAKS
ULTRAVIOLET RADIATION
XP CELLS
ANIMAL CELLS
ANIMALS
AZINES
BIOLOGICAL EFFECTS
BIOLOGICAL RECOVERY
CHEMISTRY
CONNECTIVE TISSUE CELLS
DRUGS
ELECTROMAGNETIC RADIATION
ENZYMES
HETEROCYCLIC COMPOUNDS
MAMMALS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PRIMATES
RADIATION EFFECTS
RADIATIONS
RECOVERY
REPAIR
SOMATIC CELLS
VERTEBRATES
550200* - Biochemistry
550300 - Cytology