Features and consequences for transcriptional activity of transcription factor condensation

Transcription activation relies on weak, transient interactions between the activation domains of transcription factors, general transcription factors, transcriptional co-regulators and RNA Pol II. Characterizing these interactions is important to understand the physical principles that govern this important process and, also, to identify opportunities for therapeutic intervention, especially in oncology. We are interested in characterizing how this type of interactions regulate the transcriptional activity of a specific transcription factor, the androgen receptor (AR) - the main therapeutic target for prostate cancer - and in perturbing them with small molecules. In this communication we will provide a characterization of the interactions established by the activation domain of AR [1–3] as well as evidence that the activation domain forms condensates [4] stabilized by hydrophobic interactions between partially structured motifs that are important for transcriptional activity. Finally we will put forward the hypothesis that the multivalent nature of these interactions is in part responsible for AR condensation at the initiation of transcription.

[1] E. De Mol et al., ACS Chem. Biol. 11, 2499 (2016).
[2] E. De Mol, E. Szulc et al., Structure 26, 145 (2018).
[3] L. Cato et al., Elife 6, (2017).
[4] J. J. Bouchard, J. H. Otero et al. Mol. Cell (2018).