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Solution structure of a cisplatin-induced DNA interstrand cross-link
Science (New York, N.Y.)
|December 15, 1995
Summary
Cisplatin (cis-diamminedichloroplatinum(II)) cross-links DNA, causing structural changes like minor groove binding and helix reversal. This NMR study reveals how these platinum-induced DNA adducts form and may be repaired.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Cisplatin (cis-diamminedichloroplatinum(II)) is a widely used chemotherapy drug that functions by cross-linking DNA.
- These cross-links typically occur between purine residues at the N7 atom, located in the major groove of B-form DNA.
Purpose of the Study:
- To determine the solution structure of cisplatin-cross-linked DNA using nuclear magnetic resonance (NMR).
- To elucidate the structural consequences of cis-diammineplatinum(II) interstrand cross-links in DNA.
Main Methods:
- Nuclear magnetic resonance (NMR) spectroscopy was used to determine the solution structure of a short DNA duplex cross-linked by cis-diammineplatinum(II).
- Phase-sensitive gel electrophoresis was employed to confirm DNA bending induced by the cross-links.
Main Results:
- The cis-diammineplatinum(II) adduct was found to bind in the minor groove, with complementary deoxycytidines becoming extrahelical.
- The DNA double helix adopted a locally reversed, left-handed conformation, exhibiting unwinding and bending towards the minor groove.
- NMR findings were corroborated by gel electrophoresis results, indicating significant DNA bending.
Conclusions:
- The determined NMR structure provides a detailed molecular model for cisplatin-DNA adducts, differing from previous proposals.
- This structural insight explains the observed chemical reactivity, unwinding, and bending of cis-diammineplatinum(II) cross-linked DNA.
- Understanding these structural alterations is crucial for comprehending the formation and repair mechanisms of cisplatin-induced DNA cross-links within chromatin.