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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 (... Full description

Journal Title: Proceedings of the National Academy of Sciences 05 May 2015, Vol.112(18), p.5667
Main Author: Janice Ortega
Other Authors: Jessie Y. Li , Sanghee Lee , Dan Tong , Liya Gu , Guo-Min Li
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0027-8424 ; E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1417711112
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title: Phosphorylation of PCNA by EGFR inhibits mismatch repair and promotes misincorporation during DNA synthesis
format: Article
creator:
  • Janice Ortega
  • Jessie Y. Li
  • Sanghee Lee
  • Dan Tong
  • Liya Gu
  • Guo-Min Li
subjects:
  • Sciences (General)
ispartof: Proceedings of the National Academy of Sciences, 05 May 2015, Vol.112(18), p.5667
description: 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 alpha and MutS beta and interferes with PCNA-dependent activation of MutL alpha 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.
language: eng
source:
identifier: ISSN: 0027-8424 ; E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1417711112
fulltext: fulltext_linktorsrc
issn:
  • 0027-8424
  • 00278424
  • 1091-6490
  • 10916490
url: Link


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descriptionProliferating 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 alpha and MutS beta and interferes with PCNA-dependent activation of MutL alpha 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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