The Mediator of RNA Polymerase II Transcription: Links to Transcription Elongation and Leukemogenesis

Abstract

Promoter proximal pausing by initiated RNA polymerase II (Pol II) and regulated release of paused polymerase into productive elongation has emerged as a major mechanism of transcription activation. Reactivation of paused Pol II has been shown to correlate with recruitment of a Super‐Elongation Complex or SEC that contains the transcription elongation factors ELL/EAF and P‐TEFb, as well as a collection of additional proteins encoded by genes involved in translocations with the MLL gene in leukemia. Our lab has recently obtained evidence for a role of human Mediator in recruiting SEC and another ELL/EAF‐containing complex to genes. In particular, we have shown that a conserved N‐terminal domain in the Mediator subunit Med26 provides docking sites for ELL/EAF, P‐TEFb, and associated proteins as well as the general initiation factor TFIID. Our findings are consistent with the model that Med26 functions as a molecular switch that interacts first with the Pol II initiation complex through direct interactions with TFIID and then “exchanges” TFIID for complexes containing elongation factors ELL/EAF and P‐TEFb to facilitate the transition of Pol II into the elongation stage of transcription.