DNA crosslinking

In summary, the studies of the binding of cis-and trans-DPP with the nucleosome core particle have 

ACS Symposium Series American Chemical Society Washington, DC, 1980. 

The relevance of this discovery to the cytotoxicity and greater antitumor drug action of the cis isomer is not obvious. Perhaps trans-DDP, the more reactive crosslinking reagent, is scavenged vivo before it can reach the nuclear DNA. 

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Figure 11.12 Generation and isolation of a DNA crosslinked adduct with 4-O-methylazinomycin B.

Very recently, the Shipman group have made a further step towards a comprehensive structure/activity profile for noncovalent interactions between azinomycin B and DNA [152]. They synthesized simplified azinomycin analogues 69 and 96-98 (Scheme 11.13), retaining both the epoxide and aziridine alkylating functionalities, with systematically altered substitution on the naphthoate fragment, and analyzed their DNA crosslinking by gel electrophoresis. They found that cross-... 

Although great progress has been made in study of the mode of action of the azinomycins, a full understanding of their interaction with DNA will require future structural characterization of azinomycin-DNA crosslinks by NMR or X-ray crystallography. 

DNA-DNA crosslinks develop with time following exposure to HgCl2, probably resulting from its ability to interact directly with the DNA bases [253], while single-strand breaks may result from the production of oxygen radicals by mercuric chloride and also by its interaction with DNA bases [254, 255], The single-strand breaks resemble those induced by X-rays [256]. 

Hansson J, Lewensohn R, Ringborg U, Nilsson B (1987) Eormation and removal of DNA crosslinks induced by melphalan and nitrogen mustard in relation to drug-induced cytotoxicity in human... 

Keyes SR, Loomis R, DiGiovanna MP, Pritsos CA, Rockwell S, Sartorelli AC (1991) Cytotoxicity and DNA crosslinks produced by mitomycin analogs in aerobic and hypoxic EMT6 cells. Cancer Commun 3(10-11) 351-356... 

Importantly, the ERCCl/XPF structure-specific nuclease has an additional role in the repair of cisplatin adducts besides its function in NER the recombinational repair of interstrand crosslinks (19). ERCCl- or XPF-deficient hamster mutant cell lines are hypersensitive to DNA crosslink agents, much more so than to ultraviolet-induced pyrimide dimers, the classical substrates for NER (20,21). Moreover, co-localization of ERCCl foci and RAD51 foci in response to cisplatin treatment has recently been found and may represent recruitment of ERCCl/XPF to sites of recombination repair (22). Previous studies have shown that BRCAl, involved in homologous recombination repair, also plays a major role in the repair of cisplatin DNA damage (23). 

Ristau, C., Deutschmann, S., Laib, R.J. Ottenwalder, H. (1990) Detection of diepoxybutane-induced DNA-DNA crosslinks by cesium trifluoracetate (CsTFA) density-gradient centrifugation. Arch. Toxicol., 64, 343-344... 

Mitomycin C, 1, is a potent antitumor antibiotic discovered by Japanese scientists in fermentation cultures of Streptomyces caespitosus. It has been described as "small, fast and deadly (but very selective)" and has an extraordinary ability to crosslink the complementary strands of the DNA double helix with high efficiency and absolute specificity. It is so lethal that one crosslink per genome is sufficient to cause death of a bacterial cell. Mitomycin C, which is widely used clinically as an antitumor drug, does not react with DNA, but enzymatic reduction of the quinone induces a cascade of transformations which results, ultimately, in formation of the DNA crosslink 2. 

Schuessler FI, Schmerler-Dremel G, Danzer J.Jung-Korner E (1992) Ethanol radical-induced protein-DNA crosslinking. A radiolysis study. Int J Radiat Biol 62 517-526 Schuessler FI, Distel L, Sieber R (1997) Radiolysis of DNA in the presence of a protein studied by HPL-gel chromatography. Int J Radiat Biol 71 543-553... 

Schuster GB, Landman U (2004) The mechanism of long-distance radical cation transport in duplex DNA Ion-gated hopping of polaron-like distortions. Top Curr Chem 236 139-161 Schussler H, Jung E (1989) Protein-DNA crosslinks induced by primary and secondary radicals. Int J Radiat Biol 56 423-435... 

Crosslinking or entrapment Entrapment in dextran matrix, polyacrylamide or DNA crosslinked by using some agents such as glutar aldehyde [43] ... 

Fig. 7. Schematic representation of cisplatin bonding to DNA. (1) monofunctional binding (X = Cr, OH", OH2) (2) interstrand crosslinking (3) protein-DNA crosslinking (4) intrastrand crosslinking between adjacent guanines (5) intrastrand crosslinking between two guanines separated by a third base (6) intrastrand crosslinking at a-AG-unit...

Rat liver and kidney nuclei (intraperitoneal exposure) DNA crosslinks, DNA-protein crosslinks, DNA strain breaks Cupo and Wetterhahn 1985 (III) Chromium oxide... 

Human lung fibroblasts DNA polymerase arrest, DNA-DNA crosslinks No data + Xu et al. 1996 Sodium chromate... 

Patierno SR George Washington University DNA crosslinking in chromium toxicity and carcinogenesis NIEHS... 

Lin X, Zhuang Z, Costa M. 1992. Analysis of residual amino acid-DNA crosslinks induced in intact cells by nickel and chromium compounds. Carcinogenesis 3(10) 1763-1768. 

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