NUCLEOTIDE SUBSTITUTIONS DIFFERENTIALLY AFFECT DIRECT REPEAT AND PALINDROMIC THYROID-HORMONE RESPONSE ELEMENTS

Thyroid hormone receptors are transcription factors that bind to speci fic DNA sequences and regulate gene expression in a ligand-dependent m anner. Thyroid hormone response elements can be composed of direct rep eat or palindromic arrangements of half-sites. The traditional half-si te has been considered to be the sequence 5'-AGGTCA, although we recen tly demonstrated that the optimal monomer-binding site is 2 base pairs larger, 5'-TAAGGTCA. It has generally been presumed that alterations in half-site sequence have commensurate effects on gene expression fro m direct repeat and palindromic response elements. However, in the pre sent studies we demonstrate that palindromic elements are highly depen dent on the presence of the two 5'-nucleotides (TA) for function, wher eas this portion of the response element has minimal influence on horm one induction from direct repeat elements. Hormone induction correlate s poorly with binding affinity for thyroid hormone receptor monomers, homodimers, or heterodimers with retinoid X receptors, either in the a bsence or presence of ligands. We speculate that the magnitude of horm one induction may reflect protein conformation differences induced by a combination of the presence of the appropriate 5'-nucleotides plus h alf-site orientation.