The Mechanism by which TATA-Box Polymorphisms Associated with Human Hereditary Diseases Influence Interactions with the TATA-Binding Protein

Abstract

SNPs in ТАТА boxes are the cause of monogenic diseases, contribute to a large number of complex diseases, and have implications for human sensitivity to external and internal environmental signals. The aim of this work was to explore the kinetic characteristics of the formation of human ТВР complexes with ТАТА boxes, in which the SNPs are associated with β-thalassemias of diverse severity, immunosuppression, neurological disorders, and so on. It has for the first time been demonstrated, using an electrophoretic mobility shift assay, that TBP interacts with SNP-containing ТАТА boxes with a significant (8-36-fold) decrease in TBP/ТАТА association rate constant (ka ) as compared with that in healthy people, a smaller decrease in dissociation rate constant (kd ) and changes in the half-lives of TBP/ТАТА complexes. Carriers of the -24G allele (rs 1800202T>G) in the TATA box of the triosephosphate isomerase gene promoter, associated with neurological and muscular disorders, were observed to have a 36-fold decrease in TBP/TATA association rate constant that are consistent with TPI deficiency shown for patients who carry this defective allele. The kinetic characteristics of TBP/ТАТА complexes obtained suggest that, at a molecular level, hereditary diseases are largely caused by changes in TBP/ТАТА association rates and these changes have a bearing on disease severity.