Effect of DNA polymerases and high mobility group protein 1 on the carrier ligand specificity for translesion synthesis past platinum-DNA adducts

Biochemistry. 1999 Aug 24;38(34):11026-39. doi: 10.1021/bi9909187.

Abstract

Translesion synthesis past Pt-DNA adducts can affect both the cytotoxicity and mutagenicity of the platinum adducts. We have shown previously that the extent of replicative bypass in vivo is influenced by the carrier ligand of platinum adducts. The specificity of replicative bypass may be determined by the DNA polymerase complexes that catalyze translesion synthesis past Pt-DNA adducts and/or by DNA damage-recognition proteins that bind to the Pt-DNA adducts and block translesion replication. In the present study, primer extension on DNA templates containing site-specifically placed cisplatin, oxaliplatin, JM216, or chlorodiethylenetriamine-Pt adducts revealed that the eukaryotic DNA polymerases beta, zeta, gamma, and human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) had a similar specificity for translesion synthesis past Pt-DNA adducts (dien >> oxaliplatin >/= cisplatin > JM216). Primer extension assays performed in the presence of high mobility group protein 1 (HMG1), which is known to recognize cisplatin-damaged DNA, revealed that inhibition of translesion synthesis by HMG1 also depended on the carrier ligand of the Pt-DNA adduct (cisplatin > oxaliplatin = JM216 >> dien). These data were consistent with the results of gel-shift experiments showing similar differences in the affinity of HMG1 for DNA modified with the different platinum adducts. Our studies show that both DNA polymerases and damage-recognition proteins can impart specificity to replicative bypass of Pt-DNA adducts. This information may serve as a model for further studies of translesion synthesis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism*
  • Catalysis
  • Cisplatin / chemistry
  • Cisplatin / metabolism*
  • DNA Adducts / chemistry
  • DNA Adducts / metabolism*
  • DNA Damage*
  • DNA Polymerase beta / metabolism
  • DNA Polymerase gamma
  • DNA Primers / metabolism
  • DNA Replication*
  • DNA-Directed DNA Polymerase / chemistry
  • DNA-Directed DNA Polymerase / metabolism*
  • HIV Reverse Transcriptase / metabolism
  • High Mobility Group Proteins / chemistry
  • High Mobility Group Proteins / metabolism*
  • Humans
  • Ligands
  • Molecular Sequence Data
  • Protein Binding
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae Proteins*

Substances

  • Carrier Proteins
  • DNA Adducts
  • DNA Primers
  • High Mobility Group Proteins
  • Ligands
  • Saccharomyces cerevisiae Proteins
  • cisplatin-DNA adduct
  • DNA Polymerase beta
  • HIV Reverse Transcriptase
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • POL4 protein, S cerevisiae
  • Cisplatin