Cisplatin protein recognition

The unwinding of the helix at the site of platination is 25°. The curvature and shape of the platinated duplex are remarkably similar to those observed in DNA duplexes complexed by the HMG-domain proteins revealing that cisplatin binding alters DNA in such a manner as to facilitate HMG-domain protein recognition as mentioned in the previous paragraph. 

Dunham, S.U. and Lippard, S.J. (1997) DNA sequence context and protein composition modulate HMG-domain protein recognition of cisplatin-modified DNA. Biochemistry 36, 11428-11436. 

Cellular sensitivity to different platinum compounds and the recognition of the platinum DNA adducts by mismatch repair protein complexes appear to be linked [103]. It may also be significant that hMSH2 is expressed to higher levels in testicular and ovarian tissue than in other organs such as heart, liver and colon [109], Whether or not mismatch repair plays a general role in the anticancer activity of cisplatin still remains debatable, however. Mismatch repair proteins bind to cisplatin-DNA adducts in vitro with weak specificity [109][113]. Although specificity is enhanced when aplat-inum lesion is combined with a mutation [113], it is still less than the affinity of these proteins for the unplatinated mutation [63] [108]. 

However, much data has been accumulated in recent years indicating that the replication machinery can elongate past cisplatin-DNA lesions in a mutagenic way [15], Intervention of specific DNA polymerases and protein-protein interactions between replicative enzymes and DNA damage-recognition proteins may lead to occasional translesion DNA synthesis. This translesion synthesis can occur in an error-prone fashion, leading to indue-... 

The altered structure of the DNA duplex attracts proteins involved in DNA damage recognition and high-mobility group domain (HMG) proteins, which have been postulated to mediate the antitumor activity of cisplatin. 

Cells deficient in DNA repair are hypersensitive to cisplatin and some cisplatin-resistant cell lines show increased DNA repair and increased expression of the DNA. Platinum-induced DNA lesions are primarily repaired by the NER system. This system involves more than 20 proteins responsible for damage recognition, incision of the DNA strand on both sides of the lesion, removal of the damaged bases, and finally ligation by a DNA ligase. 

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