Human multi-domain-containing protein UHRF1 has recently been extensively
characterized as a key epigenetic regulator for maintaining DNA methylation
patterns. UHRF1 SRA domain preferentially binds to hemimethylated CpG sites, and
double Tudor domain has been implicated in recognizing H3K9me3 mark, but the
role of the adjacent PHD finger remains unclear. Here, we report the
high-resolution crystal structure of UHRF1 PHD finger in complex with N-terminal
tail of histone H3. We found that the preceding zinc-Cys4 knuckle is
indispensable for the PHD finger of UHRF1 to recognize the first four unmodified
residues of histone H3 N-terminal tail. Quantitative binding studies indicated
that UHRF1 PHD finger (including the preceding zinc-Cys4 knuckle) acts together
with the adjacent double Tudor domain to specifically recognize the H3K9me3
mark. Combinatorial recognition of H3K9me3-containing histone H3 tail by UHRF1
PHD finger and double Tudor domain may play a role in establishing and
maintaining histone H3K9 methylation patterns during the cell cycle.
