Filia Is an ESC-Specific Regulator of DNA Damage Response and Safeguards Genomic Stability

Cell Stem Cell. 2015 Jun 4;16(6):684-98. doi: 10.1016/j.stem.2015.03.017. Epub 2015 Apr 30.

Abstract

Pluripotent stem cells (PSCs) hold great promise in cell-based therapy, but the genomic instability seen in culture hampers their full application. A greater understanding of the factors that regulate genomic stability in PSCs could help address this issue. Here we describe the identification of Filia as a specific regulator of genomic stability in mouse embryonic stem cells (ESCs). Filia expression is induced by genotoxic stress. Filia promotes centrosome integrity and regulates the DNA damage response (DDR) through multiple pathways, including DDR signaling, cell-cycle checkpoints and damage repair, ESC differentiation, and apoptosis. Filia depletion causes ESC genomic instability, induces resistance to apoptosis, and promotes malignant transformation. As part of its role in DDR, Filia interacts with PARP1 and stimulates its enzymatic activity. Filia also constitutively resides on centrosomes and translocates to DNA damage sites and mitochondria, consistent with its multifaceted roles in regulating centrosome integrity, damage repair, and apoptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Cell Cycle Checkpoints / drug effects
  • Cell Differentiation / drug effects
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Centrosome / drug effects
  • Centrosome / metabolism
  • Checkpoint Kinase 2 / metabolism
  • DNA Damage*
  • DNA Repair / drug effects
  • Genomic Instability* / drug effects
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / drug effects
  • Mouse Embryonic Stem Cells / metabolism*
  • Mutagens / toxicity
  • Phosphorylation / drug effects
  • Phosphoserine / metabolism
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Binding / drug effects
  • Protein Transport / drug effects
  • Proteins / metabolism*
  • Signal Transduction / drug effects
  • Subcellular Fractions / drug effects
  • Subcellular Fractions / metabolism
  • Up-Regulation / drug effects

Substances

  • Mutagens
  • Proteins
  • filia protein, mouse
  • Phosphoserine
  • Poly(ADP-ribose) Polymerases
  • Checkpoint Kinase 2
  • Ataxia Telangiectasia Mutated Proteins