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Nucleic Acids Research Advance Access originally published online on February 28, 2007
Nucleic Acids Research 2007 35(6):1812-1821; doi:10.1093/nar/gkm032
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Nucleic Acids Research, 2007, Vol. 35, No. 6 1812-1821
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Chemistry

Mechanism of the formation of DNA–protein cross-links by antitumor cisplatin

Katerina Chválová, Viktor Brabec and Jana Kaspárková*

Institute of Biophysics, Academy of Sciences of the Czech Republic, Královopolská 135, CZ-61265 Brno, Czech Republic

*To whom correspondence should be addressed. Tel: +420 541517174; Fax: +420 541240499; Email: jana{at}ibp.cz

Received October 5, 2006. Revised January 2, 2007. Accepted January 5, 2007.

DNA–protein cross-links are formed by various DNA-damaging agents including antitumor platinum drugs. The natures of these ternary DNA–Pt–protein complexes (DPCLs) can be inferred, yet much remains to be learned about their structures and mechanisms of formation. We investigated the origin of these DPCLs and their cellular processing on molecular level using gel electrophoresis shift assay. We show that in cell-free media cisplatin [cis-diamminedichloridoplatinum(II)] forms DPCLs more effectively than ineffective transplatin [trans-diamminedichloridoplatinum(II)]. Mechanisms of transformation of individual types of plain DNA adducts of the platinum complexes into the DPCLs in the presence of several DNA-binding proteins have been also investigated. The DPCLs are formed by the transformation of DNA monofunctional and intrastrand cross-links of cisplatin. In contrast, interstrand cross-links of cisplatin and monofunctional adducts of transplatin are stable in presence of the proteins. The DPCLs formed by cisplatin inhibit DNA polymerization or removal of these ternary lesions from DNA by nucleotide excision repair system more effectively than plain DNA intrastrand or monofunctional adducts. Thus, the bulky DNA–protein cross-links formed by cisplatin represent a more distinct and persisting structural motif recognized by the components of downstream cellular systems processing DNA damage considerably differently than the plain DNA adducts of this metallodrug.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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