Effects of the anticancer drug cis-diamminedichloroplatinum(II) on the activities of calf thymus DNA polymerase

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

Research output: Contribution to journalArticle

28 Citations (Scopus)

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 ε 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
StatePublished - 1993
Externally publishedYes

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DNA-Directed DNA Polymerase
Cisplatin
Guanine
DNA
Phosphodiesterase I
Pharmaceutical Preparations
Repair
DNA Repair
DNA Repair Enzymes
Exonucleases
DNA Adducts
Guanosine
Eukaryotic Cells
DNA Replication
Oligonucleotides
calf thymus DNA
Nucleotides
Enzymes

ASJC Scopus subject areas

  • Biochemistry

Cite this

Effects of the anticancer drug cis-diamminedichloroplatinum(II) on the activities of calf thymus DNA polymerase. / Huang, Lin; Turchi, John; Wahl, Alan F.; Bambara, Robert A.

In: Biochemistry, Vol. 32, No. 3, 1993, p. 841-848.

Research output: Contribution to journalArticle

Huang, Lin ; Turchi, John ; Wahl, Alan F. ; Bambara, Robert A. / Effects of the anticancer drug cis-diamminedichloroplatinum(II) on the activities of calf thymus DNA polymerase. In: Biochemistry. 1993 ; Vol. 32, No. 3. pp. 841-848.
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