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Methylation of FEN1 suppresses nearby phosphorylation and facilitates PCNA binding

Zhigang Guo1, Li Zheng, Hong Xu

  • 1Department of Cancer Biology, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA.

Nature Chemical Biology
|August 24, 2010
PubMed

Insights

Flap endonuclease 1 (FEN1) methylation regulates its interaction with PCNA, controlling DNA replication and repair timing. Disrupting this methylation causes DNA repair defects and genome instability.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cell Biology

Background:

  • Flap endonuclease 1 (FEN1) is a crucial enzyme regulating DNA replication and cell death.
  • Precise regulation of FEN1 activity is essential for proper cellular function.

Purpose of the Study:

  • To investigate the regulatory mechanisms of FEN1, focusing on post-translational modifications.
  • To elucidate the role of FEN1 methylation in its function and interaction with other proteins.

Main Methods:

  • Site-directed mutagenesis to disrupt arginine methylation sites on FEN1.
  • Analysis of FEN1 phosphorylation, PCNA interaction, and subcellular localization.
  • Assessment of DNA replication, repair, and cell cycle progression in FEN1 mutant cells.

Main Results:

  • FEN1 is methylated at arginine residues, primarily Arg192, which suppresses phosphorylation at Ser187.
  • Methylated FEN1 exhibits strong interaction with proliferating cell nuclear antigen (PCNA), regulating its enzymatic activity.
  • Mutations disrupting methylation and PCNA interaction lead to unscheduled phosphorylation, mislocalization, and impaired DNA repair.

Conclusions:

  • Arginine methylation is a critical regulatory mechanism for FEN1 function.
  • FEN1 methylation controls its interaction with PCNA, ensuring proper timing of DNA replication and repair.
  • Dysregulation of FEN1 methylation leads to genomic instability and cell cycle defects.

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