Fig. 2.

The regulation of Set2 and H3K36 methylation. Many factors come together to regulate Set2 and the production of H3K36 methylation in budding yeast. Kin28 of TFIIH initiates transcriptional initiation through the phosphorylation of the RNA polymerase II (RNAPII) C-terminal domain (CTD) at serine 5 (Ser5). This phosphorylation is important for the recruitment of Spt4/5, the Bur1 kinase, and the Paf1 complex (Paf1C) that promote transcription elongation and downstream histone modifications such as H2BK123 mono-ubiquitylation and H3K4 and K79 methylation. In addition to Kin28, Bur1 also functions to recruit the Paf1 complex, most likely through the combined actions of Bur1 activity on the CTD and the C-terminal repeat region (CTR) in Spt5. Significantly, Paf1C associates with Spt6 and stabilizes Spt6 protein levels, which is required for stabilization and function of the major Ser2 CTD kinase, Ctk1—thus creating a feed forward circuit as Ser2 CTD phosphorylation is also required for binding and stability of Spt6. These actions drive robust CTD Ser2 phosphorylation that is required for SRI–CTD interaction, which stabilizes Set2 for nucleosomal H3K36 methylation (see text for details)