CADMIUM SUBSTITUTION FOR ZINC IN FINGER-LOOP DOMAINS OF GENE-REGULATING PROTEINS AS A POSSIBLE MECHANISM FOR THE GENOTOXICITY AND CARCINOGENICITY OF CADMIUM COMPOUNDS

Certain DNA-binding proteins that control gene expression contain single or multiple copies of short polypeptide sequences approximately 30 residues long containing four Cys or His residues at defined spacing so that Zn++is complexed in tetrahedral coordination with thiol-sulfur or imidazole-nitrogen atoms. The Zn + +serves as a “strut” that stabilizes folding of the domain into a “finger-loop” which is capable of site-specific binding to double-stranded DNA. Since finger-loops provide a molecular means to regulate genetic transcription finger-loop domains have been highly conserved during evolution. The present paper reviews the in vitro evidence that Cd+ +can substitute for Zn+ +in coordination sites of finger-loop domains and suggests that in vivo occurrence of such substitution could result in genotoxicity. Cd++substitution for Zn++in finger-loop domains of transforming proteins encoded by oncogenes is proposed as an hypothetical mechanism of cadmium carcinogenesis. © 1990, Taylor & Francis Group, LLC. All rights reserved.