The Rules of DNA Recognition by the Androgen Receptor

Abstract

The androgen receptor (AR) and glucocorticoid, progestagen, and mineralocorticoid receptors all recognize classical DNA response elements that are organized as inverted repeats of 5'-AGAACA-3'-like motifs with a three-nucleotide spacer. Next to such elements, the AR also recognizes a second type of androgen response element (ARE), the so-called selective AREs, which resemble more the direct repeats of the same hexamer. In this work, we show that not only the AR but also the progestagen receptor can recognize the selective AREs, whereas neither glucocorticoid nor mineralocorticoid receptor can. Recently, genomic AR-binding fragments have been postulated to contain AR-binding sites that diverge considerably from the classical ARE consensus. Extensive mutational analyses of these candidate motifs, however, reinstalls the values of the consensus sequence for the AREs as mentioned above, the importance of their dimeric nature and the presence of exactly three-nucleotide spacing. We developed a position-specific probability matrix that was used to predict with higher accuracy new AREs in different AR-binding regions. So far, all AR-binding genomic fragments that were analyzed contain AREs defined as receptor-dimer binding motifs with the ability to confer responsiveness to a reporter gene.