Figure 6.

TFIIH-mediated phosphorylation of AR regulates its turnover by triggering its degradation by the ubiquitin/proteasome pathway. Upon the DHT ligand induction, the transactivation complex is formed once AR homodimer has targeted its responsive element (ARE) at the PSA promoter; co-factors are assembled at the promoter together with RNA pol II and the general transcription factors (GTFs) including TFIIH. In WT cells, the AR/S515 phosphorylation by TFIIH (via its cdk7 subunit) promotes the recruitment of both MDM2 E3 ligase that helps for AR polyubiquitination and the proteasome. In XPD cells (bearing the XPD/R683W mutation), AR/S515 phosphorylation is strongly inhibited, preventing the recruitment of MDM2. The E3 ligase CHIP is thus preferentially recruited, which allows with a lesser efficiency the AR polyubiquitin/proteasome process resulting in a much slower turnover.