TFIIIC35 Inhibitors

Chemical inhibitors of TFIIIC35 act through diverse mechanisms to inhibit its function in the transcription initiation complex. Plumbagin can intercalate into DNA, disrupting the DNA-binding activity of TFIIIC35, which is essential for its role in transcription initiation. Actinomycin D also targets DNA but does so by binding directly at the transcription initiation site, thereby blocking TFIIIC35 from accessing its necessary binding regions on the DNA strand. Similarly, Mithramycin A binds to DNA in GC-rich sequences, which could alter the DNA structure in such a way that impedes TFIIIC35 function. Mitoxantrone and Etoposide exert their inhibitory actions by intercalating into DNA and inhibiting topoisomerase II, respectively, leading to DNA breaks and a consequent reduction in the availability of intact DNA templates that TFIIIC35 requires for initiating transcription.

Other inhibitors affect TFIIIC35 by targeting the transcription machinery or related processes. α-Amanitin hinders RNA polymerase II, indirectly affecting TFIIIC35 by curtailing the transcription of genes necessary for its function. DRB inhibits the phosphorylation of RNA polymerase II, essential for the transition from initiation to elongation in transcription, thereby indirectly affecting TFIIIC35's role in transcription complexes. Triptolide, while not as direct, impairs the binding of TFIIIC35 to DNA by inhibiting the transcription factor's function overall. ICRF-193 acts by stabilizing the closed clamp form of topoisomerase II, reducing the availability of relaxed DNA, which is necessary for TFIIIC35 to form initiation complexes. Trichostatin A inhibits histone deacetylases, leading to a more open chromatin structure that can disrupt the normal function of TFIIIC35. Finally, Chloroquine disrupts TFIIIC35 by altering the pH of intracellular organelles and interfering with protein degradation pathways, which can lead to altered localization of TFIIIC35, ultimately inhibiting its function in transcription initiation.