Phosphorylation of PCNA by EGFR Inhibits Mismatch Repair and Promotes Misincorporation During DNA Synthesis


Proliferating cell nuclear antigen (PCNA) plays essential roles in eukaryotic cells during DNA replication, DNA mismatch repair (MMR), and other events at the replication fork. Earlier studies show that PCNA is regulated by posttranslational modifications, including phosphorylation of tyrosine 211 (Y211) by the epidermal growth factor receptor (EGFR). However, the functional significance of Y211-phosphorylated PCNA remains unknown. Here, we show that PCNA phosphorylation by EGFR alters its interaction with mismatch-recognition proteins MutSα and MutSβ and interferes with PCNA-dependent activation of MutLα endonuclease, thereby inhibiting MMR at the initiation step. Evidence is also provided that Y211-phosphorylated PCNA induces nucleotide misincorporation during DNA synthesis. These findings reveal a novel mechanism by which Y211-phosphorylated PCNA promotes cancer development and progression via facilitating error-prone DNA replication and suppressing the MMR function.

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Published in Proceedings of the National Academy of Sciences of the United States of America, v. 112, no. 18, p. 5667-5672.

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This work is supported in part by grants from the National Cancer Institute (CA167181), the National Natural Science Foundation of China (31370766 and 31461143005), and National Cancer Institute Training Grant T32 CA165990 (to J.O.). G.-M.L. holds the James-Gardner Chair in Cancer Research.