PTEN loss inhibits CHK1 to cause double stranded-DNA breaks in cells.
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.
Puc
Janusz
J
Institute for Cancer Genetics, Department of Pathology, Columbia University, New York, New York, USA.
Parsons
Ramon
R
D000595:Amino Acid Sequence; D000818:Animals; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000235:genetics*; D015536:Down-Regulation; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics*; D011485:Protein Binding; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D013234:Stem Cells / Q000528:radiation effects; D025801:Ubiquitin / Q000378:metabolism; D014466:Ultraviolet Rays
D025801:Ubiquitin; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse