EZH2 promotes DNA replication by stabilizing interaction of POLδ and PCNA via methylation-mediated PCNA trimerization

Proliferating cell nuclear antigen (PCNA), a ring-shaped homotrimer complex, promotes DNA replication via binding to DNA polymerase. Trimerized PCNA is critical for DNA replication. Enhancer of zeste homologue 2 (EZH2), which primarily acts as a histone methyltransferase, is essential for proliferation. However, how EZH2 promotes proliferation by controlling DNA replication through PCNA remains elusive.

Here, we showed that low EZH2 levels repressed the proliferation of human dental pulp cells (hDPCs). The EZH2 protein level was dramatically upregulated in hDPCs at S phase in the absence of H3K27 trimethylation. Molecularly, EZH2 interacted with PCNA via the PIP box and dimethylated PCNA at lysine 110. Dimethylation of PCNA is essential for stabilization of the PCNA trimer and the binding of DNA polymerase δ to PCNA.

Our data reveal the direct interaction between PCNA and EZH2 and a novel mechanism by which EZH2 orchestrates genome duplication.