gamma-H2AX dephosphorylation by protein phosphatase 2A facilitates DNA double-strand break repair

Mol Cell. 2005 Dec 9;20(5):801-9. doi: 10.1016/j.molcel.2005.10.003. Epub 2005 Nov 28.

Abstract

Phosphorylated histone H2AX (gamma-H2AX) forms foci over large chromatin domains surrounding double-stranded DNA breaks (DSB). These foci recruit DSB repair proteins and dissolve during or after repair is completed. How gamma-H2AX is removed from chromatin remains unknown. Here, we show that protein phosphatase 2A (PP2A) is involved in removing gamma-H2AX foci. The PP2A catalytic subunit [PP2A(C)] and gamma-H2AX coimmunoprecipitate and colocalize in DNA damage foci and PP2A dephosphorylates gamma-H2AX in vitro. The recruitment of PP2A(C) to DNA damage foci is H2AX dependent. When PP2A(C) is inhibited or silenced by RNA interference, gamma-H2AX foci persist, DNA repair is inefficient, and cells are hypersensitive to DNA damage. The effect of PP2A on gamma-H2AX levels is independent of ATM, ATR, or DNA-PK activity.

Publication types

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

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • DNA Damage*
  • DNA Repair*
  • DNA-Activated Protein Kinase / metabolism
  • DNA-Binding Proteins / metabolism
  • Fibroblasts
  • HeLa Cells
  • Histones / deficiency
  • Histones / metabolism*
  • Humans
  • In Vitro Techniques
  • Mice
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation
  • Protein Phosphatase 2
  • Protein-Serine-Threonine Kinases / metabolism
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • H2AX protein, human
  • Histones
  • Tumor Suppressor Proteins
  • gamma-H2AX protein, mouse
  • Atr protein, mouse
  • ATM protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • DNA-Activated Protein Kinase
  • Protein-Serine-Threonine Kinases
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2