期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：18
页码：5667-5672
DOI：10.1073/pnas.1417711112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceDNA replication accuracy is critical for genetic stability and is ensured by high-fidelity replicative DNA polymerases and the mismatch repair (MMR) system, both of which are regulated by the proliferating cell nuclear antigen (PCNA). Dysfunction of either system leads to genome instability and cancer development. Interestingly, many types of cancers have no obvious defects in either system, but they display increased mutation frequency during development. The underlying mechanism is unknown. We demonstrate here that PCNA tyrosine phosphorylation by epidermal growth factor receptor (EGFR) inhibits MMR and promotes misincorporation during DNA synthesis. This study therefore discovers a novel mechanism promoting genome instability and explains why progression of many cancer types is associated with EGFR overexpression and/or activation. 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 MutS and MutS{beta} and interferes with PCNA-dependent activation of MutL 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.
