DNA-DNA interstrand cross-linking by cis-diamminedichloroplatinum(II): N7(dG)-to-N7(dG) cross-linking at 5'-d(GC) in synthetic oligonucleotides.
Bioorg Med Chem
; 3(6): 659-69, 1995 Jun.
Article
em En
| MEDLINE
| ID: mdl-7582944
ABSTRACT
The nucleotide sequence specificity of the DNA-DNA interstrand cross-linking reaction of cis-diamminedichloroplatinum(II) (cis-DDP) was studied in synthetic oligonucleotides. Of six self-complementary DNAs tested, only those containing the central sequence 5'-d(GC) formed appreciable interstrand cross-linked product, as assayed by denaturing polyacrylamide gel electrophoresis (DPAGE). The nucleotide connectivity of the interstrand cross-link was defined by sequence random oxidative fragmentation followed by DPAGE, revealing that dG residues on opposite strands at the sequence 5'-d(GC) were connected to one another. The covalent structure of the cross-link was established following hydrolysis of the phosphodiester backbone of a structurally homogeneous sample of a cis-DDP interstrand cross-linked DNA tetradecamer. HPLC analysis of the hydrolysate returned all of the deoxynucleoside residues from the starting DNA except for two deoxyguanosine residues. Also returned was diammine-bis-[N7-(2'- deoxyguanosyl)]platinum(II)2+, identified by a combination of spectroscopic methods, and comparison to a synthetic authentic sample. This study directly establishes that cis-DDP forms interstrand cross-links at the duplex sequence 5'-d(GC), linking deoxyguanosine residues on opposite strands at N7 through a bridging platinum atom. Computer simulation of the interstrand cross-linked product using molecular mechanics energy minimization and molecular dynamics revealed significant structural reorganization at the site of the cross-link including a ca 40 degrees angle between the platinated guaninyl residues, which propagated to adjacent residues by base stacking to yield duplexes bent by some 30 degrees toward the major groove.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA
/
Cisplatino
/
Antineoplásicos
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
1995
Tipo de documento:
Article
País de afiliação:
Estados Unidos