Recognition of major DNA adducts of enantiomeric cisplatin analogs by HMG box proteins and nucleotide excision repair of these adducts
We examined HIVIG domain protein recognition of major 1,2-GG intrastrand DNA crosslinks, formed by two bifunctional enantionneric analogs of antitumor cis-diamminedichloroplatinum(II) (cisplatin), and removal of these crosslinks during in vitro nucleotide excision repair (NER) reactions. Electrophoretic mobility shift assays show that domains A and B of HMGB1 protein bind to (2R,3R)-diaminobutanedichloroplatinum(II)generated crosslinks with a higher affinity than to those generated by (2S,3S)-diaminobutanedichloroplatinum(II). The crosslinks of both enantionners are removed by NER with a similar efficiency; however, HMG1B protein significantly inhibits removal of the (2R,3R)-diaminobutaneplatinum(II) adduct, but not that of the (2S,3S) enantiomer. Thus, HIVIG domain proteins discriminate among different conformations of the 1,2-GG intrastrand crosslinks of the two enantionneric analogs of cisplatin, which results in different NER of these crosslinks. This observation may provide insight into the mechanisms underlying antitumor activity of cisplatin and its analogs.