Catalytic pocket of Clr4 (Suv39h) methyltransfer-ase serves as a substrate receptor for Cullin 4-dependent histone H3 ubiquitination.

Histone H3 lysine 9 (H3K9) methylation must be regulated to prevent inappropriate heterochromatin for-mation. Regulation of the conserved fission yeast H3K9 methyltransferase Clr4 (Suv39h) involves an au-tomethylation-induced conformational switch and interaction of its catalytic SET domain with mono-ubiquitinated histone H3 lysine 14 (H3K14ub), a modification catalyzed by the Cul4 subunit of the CLRC complex. Using reconstituted CLRC, we show that Clr4 catalytic pocket serves as a substrate receptor for Cul4-dependent H3K14 ubiquitination.