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

摘要

SNPs in TATA 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 TVR complexes with TATA 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 TATA boxes with a significant (8-36-fold) decrease in TBP/TATA 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/TATA complexes. Carriers of the -24G allele (rs 1800202TG) 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/TATA complexes obtained suggest that, at a molecular level, hereditary diseases are largely caused by changes in TBP/TATA association rates and these changes have a bearing on disease severity.