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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. Unique Identifier : AIDSLINE

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.

JOURNAL ARTICLE Base Sequence Carrier Proteins/CHEMISTRY/*METABOLISM Catalysis Cisplatin/CHEMISTRY/*METABOLISM Comparative Study DNA Adducts/CHEMISTRY/*METABOLISM *DNA Damage DNA Polymerase beta/METABOLISM DNA Primers/METABOLISM *DNA Replication DNA-Directed DNA Polymerase/CHEMISTRY/*METABOLISM High Mobility Group Proteins/CHEMISTRY/*METABOLISM Human HIV-1 Reverse Transcriptase/METABOLISM Ligands Molecular Sequence Data Protein Binding Saccharomyces cerevisiae/ENZYMOLOGY Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S.


Information in this article was accurate in November 30, 1999. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.