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Titolo:
Transcriptional blockages in a cell-free system by sequence-selective DNA alkylating agents
Autore:
Ferguson, LR; Liu, AP; Denny, WA; Cullinane, C; Talarico, T; Phillips, DR;
Indirizzi:
Univ Auckland, Fac Med & Hlth Sci, Auckland Canc Soc Res Ctr, Auckland 1000, New Zealand Univ Auckland Auckland New Zealand 1000 Ctr, Auckland 1000, New Zealand La Trobe Univ, Dept Biochem, Bundoora, Vic 3083, Australia La Trobe Univ Bundoora Vic Australia 3083 , Bundoora, Vic 3083, Australia
Titolo Testata:
CHEMICO-BIOLOGICAL INTERACTIONS
fascicolo: 1, volume: 126, anno: 2000,
pagine: 15 - 31
SICI:
0009-2797(20000414)126:1<15:TBIACS>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
NITROGEN-MUSTARD; ADDUCTS; GROOVE; HOECHST-33258; TERMINATION; PIBENZIMOL; INITIATION; ELONGATION; CISPLATIN; ANALOGS;
Keywords:
transcription blockage; cisplatin; chlorambucil; cyclopropylindoline; bisbenzimidazole; DNA minor groove binding alkylator;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
24
Recensione:
Indirizzi per estratti:
Indirizzo: Ferguson, LR Univ Auckland, Fac Med & Hlth Sci, Auckland Canc Soc Res Ctr,Private Bag 92019, Auckland 1000, New Zealand Univ Auckland Private Bag 92019 Auckland New Zealand 1000 nd
Citazione:
L.R. Ferguson et al., "Transcriptional blockages in a cell-free system by sequence-selective DNA alkylating agents", CHEM-BIO IN, 126(1), 2000, pp. 15-31

Abstract

There is considerable interest in DNA sequence-selective DNA-binding drugsas potential inhibitors of gene expression. Five compounds with distinctlydifferent base pair specificities were compared in their effects on the formation and elongation of the transcription complex from the lac UV5 promoter in a cell-free system. All were tested at drug levels which killed 90% of cells in a clonogenic survival assay. Cisplatin, a selective alkylator atpurine residues, inhibited transcription, decreasing the full-length transcript, and causing blockage at a number of GG or AG sequences, making it probable that intrastrand crosslinks are the blocking lesions. A cyclopropylindoline known to be an A-specific alkylator also inhibited transcription, with blocks at adenines. The aniline mustard chlorambucil, that targets primarily G but also A sequences, was also effective in blocking the formation of full-length transcripts. It produced transcription blocks either at, or one base prior to. AA or GG sequences, suggesting that intrastrand crosslinks could again be involved. The non-alkylating DNA minor groove binder Hoechst 33342 (a bisbenzimidazole) blocked formation of the full-length transcript, but without creating specific blockage sites. A bisbenzimidazole-linked aniline mustard analogue was a more effective transcription inhibitor than either chlorambucil or Hoechst 33342, with different blockage sites occurring immediately as compared with 2 h after incubation. The blockages were either immediately prior to AA or GG residues, or Tour to five base pairs prior to such sites, a pattern not predicted from in vitro DNA-binding studies. Minor groove DNA-binding ligands are of particular interest as inhibitors of gene expression, since they have the potential ability to bind selectively to long sequences of DNA. The results suggest that the bisbenzimidazole-linked mustard does cause alkylation and transcription blockage at novelDNA sites, in addition to sites characteristic of untargeted mustards. (C)2000 Elsevier Science Ireland Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/12/20 alle ore 18:27:28