Phosphorylation of PCNA by EGFR inhibits mismatch repair and promotes misincorporation during DNA synthesis

Janice Ortega, Jessie Y. Li, Sanghee Lee, Dan Tong, Liya Gu, Guo Min Li

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Proliferating or 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.

Original languageEnglish (US)
Pages (from-to)5667-5672
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number18
DOIs
StatePublished - May 5 2015

Keywords

  • Cancer
  • EGFR
  • Genome instability
  • Mismatch repair
  • PCNA phosphorylation

ASJC Scopus subject areas

  • General

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