Polycomb repressive complex 1 (PRC1) is required for ubiquitination of histone
H2A lysine 119, an epigenetic mark associated with repression of genes important
in developmental regulation. The E3 ligase activity of PRC1 resides in the
RING1A/B subunit when paired with one of six PCGF partners. The best known of
these is the oncogene BMI1/PCGF4. We find that canonical PRC1 E3 ligases such as
PCGF4-RING1B have intrinsically very low enzymatic activity compared with
non-canonical PRC1 RING dimers. The structure of a high-activity variant in
complex with E2 (PCGF5-RING1B-UbcH5c) reveals only subtle differences from an
earlier PCGF4 complex structure. However, two charged residues present in the
modelled interface with E2-conjugated ubiquitin prove critical: in BMI1/PCGF4,
these residues form a salt bridge that may limit efficient ubiquitin transfer.
The intrinsically low activity of the PCGF4-RING1B heterodimer is offset by a
relatively favourable interaction with nucleosome substrates, resulting in an
efficient site-specific monoubiquitination.
