PTEN loss inhibits CHK1 to cause double stranded-DNA breaks in cells

Cell Cycle. 2005 Jul;4(7):927-9. doi: 10.4161/cc.4.7.1795. Epub 2005 Jul 3.

Abstract

CHK1 is an essential kinase involved in the regulation of the cell cycle progression and preservation of genomic integrity. Inhibition of CHK1 leads to the accumulation of double-stranded DNA breaks. Loss of PTEN impairs CHK1-mediated checkpoint activation due to cytoplasmic sequestration of ubiquitinated CHK1. Here, we provide evidence that another consequence of reduced CHK1 function in PTEN deficient cells is the accumulation of double-stranded DNA breaks. Moreover, we show that the site of CHK1 ubiquitination (K274) is near the site of AKT phosphorylation (S280). Overall, these data demonstrate that lack of PTEN generates DNA damage due to inappropriate inactivation of CHK1.DNA damage due to the loss of PTEN is likely to stimulate tumor development.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Checkpoint Kinase 1
  • DNA Damage / genetics*
  • Down-Regulation
  • Mice
  • Molecular Sequence Data
  • Mutation / genetics
  • Oncogene Protein v-akt / metabolism
  • PTEN Phosphohydrolase / deficiency*
  • PTEN Phosphohydrolase / genetics*
  • Protein Binding
  • Protein Kinases / chemistry
  • Protein Kinases / metabolism*
  • Stem Cells / radiation effects
  • Ubiquitin / metabolism
  • Ultraviolet Rays

Substances

  • Ubiquitin
  • Protein Kinases
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • Oncogene Protein v-akt
  • PTEN Phosphohydrolase
  • Pten protein, mouse