DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1

Nat Cell Biol. 2002 Dec;4(12):993-7. doi: 10.1038/ncb884.

Abstract

Activation of the ataxia telangiectasia mutated (ATM) kinase triggers diverse cellular responses to ionizing radiation (IR), including the initiation of cell cycle checkpoints. Histone H2AX, p53 binding-protein 1 (53BP1) and Chk2 are targets of ATM-mediated phosphorylation, but little is known about their roles in signalling the presence of DNA damage. Here, we show that mice lacking either H2AX or 53BP1, but not Chk2, manifest a G2-M checkpoint defect close to that observed in ATM(-/-) cells after exposure to low, but not high, doses of IR. Moreover, H2AX regulates the ability of 53BP1 to efficiently accumulate into IR-induced foci. We propose that at threshold levels of DNA damage, H2AX-mediated concentration of 53BP1 at double-strand breaks is essential for the amplification of signals that might otherwise be insufficient to prevent entry of damaged cells into mitosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics*
  • Cell Line
  • Checkpoint Kinase 2
  • Chromosomal Proteins, Non-Histone
  • DNA Damage / genetics*
  • DNA-Binding Proteins
  • G2 Phase / genetics*
  • G2 Phase / physiology
  • Gene Expression Regulation
  • Histones / genetics*
  • Intracellular Signaling Peptides and Proteins*
  • Mice
  • Mitosis / genetics*
  • Mitosis / physiology
  • Phosphoproteins*
  • Phosphorylation
  • Protein Kinases / genetics
  • Protein-Serine-Threonine Kinases*
  • Tumor Suppressor p53-Binding Protein 1

Substances

  • Carrier Proteins
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Histones
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • Trp53bp1 protein, mouse
  • Tumor Suppressor p53-Binding Protein 1
  • Protein Kinases
  • Checkpoint Kinase 2
  • Chek2 protein, mouse
  • Protein-Serine-Threonine Kinases