Recognition of major DNA adducts of enantiomeric cisplatin analogs by HMG box proteins and nucleotide excision repair of these adducts.
We examined HMG domain protein recognition of major 1,2-GG intrastrand DNA crosslinks, formed by two bifunctional enantiomeric 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 enantiomers 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, HMG domain proteins discriminate among different conformations of the 1,2-GG intrastrand crosslinks of the two enantiomeric 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.
Malina
Jaroslav
J
Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, CZ-61265, Brno, Czech Republic.
Kasparkova
Jana
J
Natile
Giovanni
G
Brabec
Viktor
V
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D016466:CHO Cells; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D006224:Cricetinae; D018736:DNA Adducts / Q000378:metabolism*; D004260:DNA Repair / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D024243:HMGB1 Protein / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D015345:Oligonucleotide Probes / Q000138:chemical synthesis; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D013379:Substrate Specificity
D000970:Antineoplastic Agents; D018736:DNA Adducts; D024243:HMGB1 Protein; D015345:Oligonucleotide Probes; D011994:Recombinant Proteins; C057270:cisplatin-DNA adduct; D002945:Cisplatin