Cla4 phosphorylates histone methyltransferase Set1 to prevent its degradation by the APC/CCdh1 complex
The expression of chromatin modifying enzymes needs to be tightly controlled to ensure proper distribution of chromatin modifications. H3 lysine 4 trimethylation (H3K4me3) is a conserved histone modification catalyzed by histone methyltransferase Set1 and its dysregulation is associated with pathologies. Here, we show that Set1 is intrinsically unstable and its protein levels are strictly controlled by ubiquitin-dependent proteasomal degradation within the cell cycle and during gene transcription. Specifically, Set1 contains a destruction box (D-box) that can be recognized by the E3 ligase APC/CCdh1 complex and degraded by the ubiquitin-proteasome pathway. Cla4 phosphorylates serine 228 (S228) within Set1 D-box, which inhibits APC/CCdh1-mediated Set1 proteolysis. During gene transcription, the RNA polymerase II-associated PAF complex facilitates Cla4 to phosphorylate Set1-S228 and protect the chromatin-bound Set1 from degradation. By modulating the stability of Set1, Cla4 and the APC/CCdh1 complex control H3K4me3 levels, which then regulates gene transcription, cell cycle progression and chronological aging. In addition to Set1, there are 141 proteins containing the D-box that can be potentially phosphorylated by Cla4 to prevent their degradation by the APC/CCdh1 complex. Thus, we not only addressed the long-standing question about how Set1 stability is controlled, but also uncovered a new mechanism to regulate protein stability Overall design: ChIP-Seq examination