In Vitro Repair of Cisplatin-Dna Adducts by a Defined Enzyme System
It is now well established that DNA is the target for the cytotoxic effects of platinum anticancer drugs (1). There are molecular mechanisms that remove the Pt adducts from DNA and thus reverse the biological effects of the Pt drugs. These DNA repair mechanisms have been characterized in E. coli. Of particular interest is the nucleotide excision because this pathway has been shown to be the major repair pathway responsible for cis-DDP resistance of this organism (2). Nucleotide excision repair in E. coli is mediated by ABC excision nuclease (excinuclease) which is composed of three subunits, the UvrA, UvrB and UvrC proteins. The enzyme incises on both sides of the modified nucleotide(s) hydrolyzing the 8th phosphodiester bond 5′ (7 bases 5′) and the 4th or 5th phosphodiester bond 3′ (3 or 4 bases 3′) to the adduct (3). Thus it removes a little over one turn of DNA from the damaged strand. The resulting gap is filled in by DNA polymerases and sealed by ligase.
KeywordsNucleotide Excision Repair Phosphodiester Bond Carrier Ligand Platinum Anticancer Drug UvrC Protein
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