Abstract
Chk1, an evolutionarily conserved protein kinase, has been implicated in cell cycle checkpoint control in lower eukaryotes. By gene disruption, we show that CHK1 deficiency results in a severe proliferation defect and death in embryonic stem (ES) cells, and peri-implantation embryonic lethality in mice. Through analysis of a conditional CHK1-deficient cell line, we demonstrate that ES cells lacking Chk1 have a defective G2/M DNA damage checkpoint in response to γ-irradiation (IR). CHK1 heterozygosity modestly enhances the tumorigenesis phenotype of WNT-1 transgenic mice. We show that in human cells, Chk1 is phosphorylated on serine 345 (S345) in response to UV, IR, and hydroxyurea (HU). Overexpression of wild-type Atr enhances, whereas overexpression of the kinase-defective mutant Atr inhibits S345 phosphorylation of Chk1 induced by UV treatment. Taken together, these data indicate that Chk1 plays an essential role in the mammalian DNA damage checkpoint, embryonic development, and tumor suppression, and that Atr regulates Chk1.
Original language | English (US) |
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Pages (from-to) | 1448-1459 |
Number of pages | 12 |
Journal | Genes and Development |
Volume | 14 |
Issue number | 12 |
State | Published - Jun 15 2000 |
Keywords
- Atm
- Atr
- Checkpoint
- Chk1
- DNA damage
- Embryonic lethality
ASJC Scopus subject areas
- Genetics
- Developmental Biology