HMG-DOMAIN PROTEINS SPECIFICALLY INHIBIT THE REPAIR OF THE MAJOR DNA ADDUCT OF THE ANTICANCER DRUG CISPLATIN BY HUMAN EXCISION NUCLEASE

The most frequent DNA adduct made by the anticancer drug cisplatin, the 1,2-intrastrand d(GpG) crosslink, as well as the minor 1,3-intrastrand d(GpTpG) adduct, were both repaired by an in vitro human excision repair system. Fragments of 27-29 nt containing the platinum damage were excised. The high mobility group (HMG)-domain proteins HMG1 and human mitochondrial transcription factor specifically inhibited repair of the 1,2-intrastrand cross-link by the human excision nuclease. These results suggest that the types and levels of HMG-domain proteins in a given tumor may influence the responsiveness of that cancer to cisplatin chemotherapy and they provide a rational basis for the synthesis of new platinum anticancer drug candidates.