Regulating CTD‐Interactions by Ess1‐Dependent Prolyl Isomerization

Abstract

RNA polymerase II directs the synthesis of mRNAs as well as snoRNAs and some snRNAs. The largest subunit, Rpb1, contains an unstructured C‐terminal domain (CTD) composed of multiple repeats of the heptapeptide, Y‐S‐P‐T‐S‐P‐S. These repeats are located near the RNA exit channel and are bound by a variety of protein complexes that function during different stages of transcription and co‐transcriptional RNA processing. Despite the fact that the CTD is relatively long (26 repeats in yeast, 52 in human), different co‐factor complexes are differentially recruited to the CTD during the transcription cycle. Recruitment is regulated by covalent and non‐covalent modification of residues within the CTD repeat. This regulation is referred to as the “CTD code.” Examples of important covalent modifications are phosphorylation of serines at positions 2, 5, and 7.We are studying a non‐covalent modification, the cis/trans isomerization of the peptide bond at phosphorylated Ser5‐Pro6 sites. In yeast, this is carried out by a highly‐conserved enzyme that we discovered called Ess1 (Pin1 in humans). Ess1 binds and isomerizes pSer5‐Pro6, and this has profound consequences for the proper recruitment of proteins (e.g. Nrd1, Pcf11) to the RNAP II complex. Cells that lack Ess1 activity fail to suppress cryptic transcription, and cannot efficiently terminate transcription of small ncRNAs and mRNAs, leading to cell death. Ess1‐dependent isomerization of the CTD also seems to be important for histone modification, as ess1 mutants show reduced levels of H3K4‐ trimethylation. We will discuss potential mechanisms for how Ess1 regulates RNAP II transcription and co‐transcriptional processing.