Cisplatin, but not its trans geometric isomer, is a potent anticancer drug whose biological activity is a consequence of the formation of covalent adducts between the platinum compound and certain bases in DNA. Two classes of proteins have recently been identified that bind preferentially to damaged sites: proteins that specifically recognize those sites as a first step in their repair, and those that bind to such sites by virtue of structural similarity between the modified DNA and their own natural binding sites. Both classes of proteins may be involved, perhaps in opposing ways, in the cytotoxic effect of the drug.

The belief that histone H1 interacts primarily with DNA in chromatin and much less with the protein component has led to numerous studies of artificial H1-DNA complexes. This review summarizes and discusses the data on different aspects of the interaction between the linker histone and naked DNA, including cooperativity of binding, preference for supercoiled DNA, selectivity with respect to base composition and nucleotide sequence, and effect of H1 binding on the conformation of the underlying DNA. The nature of the interaction, the structure of the complexes, and the role histone H1 exerts in chromatin are also discussed.

Both cis-diamminedichloroplatinum(II) (cisplatin or cis-DDP) and trans-diamminedichloroplatinum (II) form covalent adducts with DNA. However, only the cis isomer is a potent anticancer agent. It has been postulated that the selective action of cis-DDP occurs through specific binding of nuclear proteins to cis-DDP-damaged DNA sites and that binding blocks DNA repair. We find that a very abundant nuclear protein, the linker histone H1, binds much more strongly to cis-platinated DNA than to trans-platinated or unmodified DNA. In competition experiments, H1 is shown to bind much more strongly than HMG1, which had been previously considered a major candidate for such binding in vivo.cis-Diamminedichloroplatinum(II) (cisplatin or cis-DDP) is a potent chemotherapeutic agent widely used in the clinical practice to treat several types of human malignancies. The therapeutic effect is believed to arise as a consequence of cis-DDP binding to DNA (1), but it cannot be solely explained on the basis of DNA binding because a number of closely related compounds, among which is included the geometric isomer trans-DDP, are not effective agents although they also damage DNA. The differential biological effect of different Pt compounds may lie in the differential processing of different Pt-DNA adducts by the cell. The realization that different adducts may be processed differently suggested that certain proteins might enhance or block DNA repair by specifically interacting with cis-DDP-modified DNA; this has focused research toward identifying such proteins.cis-DDP causes the formation of two major intrastrand DNA adducts, 1,2-d(GpG) and d(ApG) cross-links in which the two chloride ions of cis-DDP are replaced by the N7 atoms of guanine and adenine. An intrastrand cross-link may also be formed, at a much lower frequency, at d(GpXpG), where X is any base. Other minor adducts may also arise, including interstrand cross-links involving guanine residues on opposite strands. Biochemical and structural analyses of both intra-and interstrand cis-DDP adducts (2, 3) reveal major distortions of the DNA double helix, including bending and unwinding (for review, see ref. 4). The therapeutically inactive trans-DDP is incapable of forming the 1,2-(GpG) and d(ApG) adducts for stereochemical reasons. It does form 1,3-intrastrand links and also cross-links opposite strands, but although cis-DDP reacts with guanine residues in d(GpC), the trans-isomer preferentially cross-links complementary guanine and cytosine residues (5). The different kinds of cross-links created by the cis-and trans-DDP are illustrated schematically for one specific DNA fragment used in this work (see Fig. 2 A).Recent years have witnessed the discovery of a number of cellular proteins, mostly with still unidentified in vivo functions, that recognize and bind selectively to cis-DDP-modified DNA. These include the relatively abundant chromatin nonhistone proteins HMG1 and HMG2 (6, 7), the human structure-specific recognition protein 1 SSRP1 (8, 9), the yeast intrastrand c...