title: Phosphorylation of PCNA by EGFR inhibits mismatch repair and promotes misincorporation during DNA synthesis.
abstract: 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.
authors.affiliation: Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536;
authors.forename: Janice
authors.initials: J
authors.lastname: Ortega
authors.affiliation: Paul Laurence Dunbar High School, Lexington, KY 40513; and.
authors.forename: Jessie Y
authors.initials: JY
authors.lastname: Li
authors.affiliation: Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536;
authors.forename: Sanghee
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536; Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing 100084, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Tong
authors.affiliation: Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536; gmli@uky.edu lgu0@uky.edu.
authors.forename: Liya
authors.initials: L
authors.lastname: Gu
authors.affiliation: Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536; Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing 100084, China gmli@uky.edu lgu0@uky.edu.
authors.forename: Guo-Min
authors.initials: GM
authors.lastname: Li
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis*; D053843:DNA Mismatch Repair; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism*; D016678:Genome; D015894:Genome, Human; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D011485:Protein Binding; D017422:Sequence Analysis, DNA; D014443:Tyrosine / Q000737:chemistry
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D014443:Tyrosine; D004247:DNA; D066246:ErbB Receptors
keywords: EGFR; PCNA phosphorylation; cancer; genome instability; mismatch repair
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