ANALYSIS OF HMG PROTEIN-BINDING TO DNA MODIFIED WITH THE ANTICANCER DRUG CISPLATIN

Cisplatin (CDDP) is an effective and widely used cancer chemotherapy d rug. High mobility group (HMG) proteins 1 and 2 have been shown to bin d with high affinity to CDDP-DNA. In this study we analyzed the intera ction of HMG proteins with CDDP-DNA. We demonstrate that after binding , HMG proteins can be removed from CDDP-DNA leaving the Pt adducts int act and capable of rebinding HMG proteins. Furthermore, the very HMG p roteins that have been removed remain functionally viable and capable of rebinding CDDP-DNA. We also investigated the role that Cys residues play in protein binding. Replacement of Cys 45 or Cys 106 with a Ser residue reduced HMG2 protein binding to CDDP-DNA. These results indica te that Cys residues play a critical role in the high affinity binding of this protein to CDDP-DNA. From these findings, we speculate that t he intracellular oxidative environment could affect the redox state of protein thiols in HMG1 and HMG2 and in addition, regulate the ability of these proteins to recognize cis-Pt-DNA adduct formation in tumor c ells.