The Structural and Possible Functional Alterations on DNA and Chromatin Resulting fromcis-Pt(NH3)2Cl2Modification

Abstract

cis-Diamminedichloroplatinum(II) binds covalently to the bases of DNA and exhibits a number of distinct modes of binding that can influence the structure of DNA. Of these, the intrastrand crosslink to adjacent guanines appears responsible for unwinding of supercoiled DNA and stimulating S1 nuclease activity. Investigation of the binding that occurs in chromatin reveals that the antitumor drug also forms crosslinks between DNA and the HMG proteins 1, 2, and E in micrococcal nuclease-accessible regions, in addition to protein-protein crosslinks between the LMG proteins. From the studies on both DNA and chromatin, we propose 1) a model for the interaction of, and the general location of, these HMG proteins in chromatin and 2) novel mechanisms for the possible action of cis-diamminedichloroplatinum(II) in cancer chemotherapy.