POLR2D Activators

Chemical activators of POLR2D work through a variety of mechanisms to influence the activity of this subunit of RNA polymerase II. Amiloride functions by inhibiting sodium channels, leading to an increase in intracellular sodium concentrations. This alteration in the cellular ionic environment can enhance the activity of POLR2D as part of the cellular response to maintain ionic homeostasis. DRB and Flavopiridol, on the other hand, target the transcription elongation process. DRB inhibits the positive transcription elongation factor b (P-TEFb), which is essential for RNA polymerase II activation. This inhibition results in a compensatory activation of POLR2D to sustain essential transcriptional processes. Similarly, Flavopiridol inhibits CDK9 within the P-TEFb complex, which leads to the release of paused RNA polymerase II, subsequently increasing POLR2D activity as transcription is resumed.

Other chemical activators influence chromatin structure and gene expression, thereby affecting POLR2D activity. Trichostatin A, for example, inhibits histone deacetylases, resulting in a more open chromatin configuration that facilitates POLR2D access to DNA for transcription. I-BET151 and JQ1 disrupt the interaction between acetylated histones and bromodomains, enhancing the recruitment of the RNA polymerase II complex that includes POLR2D to the chromatin. C646 selectively inhibits histone acetyltransferase p300, leading to transcriptional changes that can increase the recruitment and activation of POLR2D. BIX-01294 inhibits G9a histone methyltransferase, altering chromatin in a manner that may enhance POLR2D activity. MG132, a proteasome inhibitor, results in the accrual of proteins, some of which may interact with and activate POLR2D. Cycloheximide blocks protein synthesis, leading to an increase in transcriptional activity that includes POLR2D activation. Lastly, VP16 causes DNA damage, activating POLR2D as part of the cellular response to transcribe DNA repair genes, and Pyridostatin stabilizes G-quadruplex structures, challenging the progression of RNA polymerase II and subsequently leading to POLR2D activation to resolve these structures and continue transcription.