The largest subunit of Pol II, RPB1, contains a C-terminal low-complexity domain, CTD, that is critical for pre-mRNA synthesis and co-transcriptional processing. The CTD is conserved from humans to fungi, but differs in the number of its heptapeptide repeats, with the consensus sequence YSPTSPS. Truncating the CTD of RPB1 in S. cerevisiae to fewer than 13 repeats leads to growth defects, and a minimum of eight repeats is required for yeast viability. The CTD serves as a platform for assembly of factors that regulate transcription initiation, elongation, termination and mRNA processing. Assembly of the preinitiation complex at Pol II promoters requires an unphosphorylated CTD and that subsequent CTD phosphorylation at S5 CTD residues by the cyclin-dependent kinase 7 (CDK7) in transcription factor IIH (TFIIH) stimulates the transition of Pol II into active elongation. Therefore, phosphorylation at S5 is incompatible with CTD phase separation and transfers the CTD from the highly concentrated state within droplets to the dispersed pool (PMID:30127355). Phase separated condensates formed by the LC domains of FUS, EWS and TAF15 when they are translocated onto a variety of different DNA-binding domains in oncogenic fusion proteins directly bind the C-terminal domain (CTD) of RNA polymerase II in a manner reversible by phosphorylation of the iterated, heptad repeats of the CTD (PMID:24267890, PMID:28945358). Mediator and Pol II, both of which can form small transient and large stable clusters in living embryonic stem cells, are co-localized in the stable clusters, which associate with chromatin, have properties of phase-separated condensates, and are sensitive to transcriptional inhibitors. Large clusters of Mediator, recruited by transcription factors at large or clustered enhancer elements probably interact with large Pol II clusters in transcriptional condensates in vivo (PMID:29930094).