The ESC-E(Z) complex of Drosophila melanogaster Polycomb group (PcG) repressors 
is a histone H3 methyltransferase (HMTase). This complex silences fly Hox genes, 
and related HMTases control germ line development in worms, flowering in plants, 
and X inactivation in mammals. The fly complex contains a catalytic SET domain 
subunit, E(Z), plus three noncatalytic subunits, SU(Z)12, ESC, and NURF-55. The 
four-subunit complex is >1,000-fold more active than E(Z) alone. Here we show 
that ESC and SU(Z)12 play key roles in potentiating E(Z) HMTase activity. We 
also show that loss of ESC disrupts global methylation of histone H3-lysine 27 
in fly embryos. Subunit mutations identify domains required for catalytic 
activity and/or binding to specific partners. We describe missense mutations in 
surface loops of ESC, in the CXC domain of E(Z), and in the conserved VEFS 
domain of SU(Z)12, which each disrupt HMTase activity but preserve complex 
assembly. Thus, the E(Z) SET domain requires multiple partner inputs to produce 
active HMTase. We also find that a recombinant worm complex containing the E(Z) 
homolog, MES-2, has robust HMTase activity, which depends upon both MES-6, an 
ESC homolog, and MES-3, a pioneer protein. Thus, although the fly and mammalian 
PcG complexes absolutely require SU(Z)12, the worm complex generates HMTase 
activity from a distinct partner set.