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, th e 1,2-intrastrand d(GpG) crosslink, as well as the minor 1,3-intrastra nd d(GpTpG) adduct, were both repaired by an in vitro human excision r epair system. Fragments of 27-29 nt containing the platinum damage wer e excised. The high mobility group (HMG)-domain proteins HMG1 and huma n mitochondrial transcription factor specifically inhibited repair of the 1,2-intrastrand cross-link by the human excision nuclease. These r esults suggest that the types and levels of HMG-domain proteins in a g iven tumor may influence the responsiveness of that cancer to cisplati n chemotherapy and they provide a rational basis for the synthesis of new platinum anticancer drug candidates.