Regulation of the ubiquitin ligase SCFMet30 and its connection to cell cycle control. SCFMet30 ubiquitinates the transcriptional activator Met4 on lysine 163 to maintain it in an inactive state. Degradation of poly-ubiquitinated Met4 is prevented by an ubiquitin-interacting motif (UIM) in Met4. The sulfur containing compounds methionine, cysteine, and S-adenosylmethionine stimulate Met4 ubiquitination, but when their intracellular concentrations are low, reduced ubiquitination combined with Met4 deubiquitination by a so far unidentified deubiquitinating enzyme(s) (Ubp) leads to Met4 activation. Cadmium and arsenic stress inhibit Met4 ubiquitination by inactivation of the ubiquitin ligase SCFMet30. The resulting activation of Met4 raises cellular glutathione levels due to induced expression of Gsh1. Active Met4 induces expression of a number of genes involved in the sulfur amino acid synthesis pathway (MET-genes) as well as GSH1. MET-gene expression depends on either one of the two homologous zinc-finger proteins Met31 and Met32. Met4 activation also inhibits a number of cell cycle events and can lead to cell cycle arrest. The Met4-dependent cell cycle arrest requires Met32 but cannot be mediated by Met31.