Defective S phase chromatin assembly causes DNA damage, activation of the S phase checkpoint, and S phase arrest

Mol Cell. 2003 Feb;11(2):341-51. doi: 10.1016/s1097-2765(03)00037-6.

Abstract

The S phase checkpoint protects the genome from spontaneous damage during DNA replication, although the cause of damage has been unknown. We used a dominant-negative mutant of a subunit of CAF-I, a complex that assembles newly synthesized DNA into nucleosomes, to inhibit S phase chromatin assembly and found that this induced S phase arrest. Arrest was accompanied by DNA damage and S phase checkpoint activation and required ATR or ATM kinase activity. These results show that in human cells CAF-I activity is required for completion of S phase and that a defect in chromatin assembly can itself induce DNA damage. We propose that errors in chromatin assembly, occurring spontaneously or caused by genetic mutations or environmental agents, contribute to genome instability.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins*
  • Chromatin / metabolism*
  • Chromatin Assembly Factor-1
  • Chromosomal Proteins, Non-Histone*
  • DNA Damage*
  • DNA, Neoplasm / biosynthesis
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Humans
  • Mutation
  • Protein-Serine-Threonine Kinases / metabolism
  • S Phase / genetics*
  • S Phase / physiology*
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins

Substances

  • Cell Cycle Proteins
  • Chromatin
  • Chromatin Assembly Factor-1
  • Chromosomal Proteins, Non-Histone
  • DNA, Neoplasm
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • ATM protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases