Effects of the Anticancer Drug cis-Diamminedichloroplatinum(II) on the Activities of Calf Thymus DNA Polymerase ϵ

Lin Huang, John J. Turchi, Alan F. Wahl, Robert A. Bambara

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

DNA polymerase (pol) ϵ is essential for DNA replication and is thought to be a component of DNA repair systems in eukaryotic cells. The activities of pol ϵ have been examined using a series of synthetic oligonucleotides designed with cis-diamminedichloroplatinum(II) (cis-DDP)-modified specific guanine residues. Pol ϵ was incapable of synthesis over cis-DDP-modified single guanine or adjacent guanine residues present in the template strand. Both single and double guanines modified by cis-DDP present at the 3′-OH end of a primer strand completely inhibited the synthetic activity of pol ϵ and, in addition, sequestered pol ϵ at the platinated 3′-OH termini. The sequestering of pol ϵ on cis-DDP modified DNA may interfere with the function of this enzyme in DNA repair in vivo. The intrinsic 3′ to 5′ proofreading exonuclease activity of pol e was also examined. Pol ϵ was capable of degrading a single-strand template with internal cis-DDP-modified guanines up to, but not through, the platinated nucleotides. A single platinated guanosine was sufficient to block the 3′ to 5′ exonuclease activity of pol ϵ. These results suggest that cis-DDP-DNA adducts inhibit DNA synthesis mediated by DNA polymerase ϵ and that platinated sites can arrest the nuclease of pol ϵ, a function exhibited during DNA repair.

Original languageEnglish (US)
Pages (from-to)841-848
Number of pages8
JournalBiochemistry
Volume32
Issue number3
DOIs
StatePublished - 1993

ASJC Scopus subject areas

  • Biochemistry

Fingerprint Dive into the research topics of 'Effects of the Anticancer Drug cis-Diamminedichloroplatinum(II) on the Activities of Calf Thymus DNA Polymerase ϵ'. Together they form a unique fingerprint.

  • Cite this