Chk1 is an essential kinase that is regulated by Atr and required for the G2/M DNA damage checkpoint

Qinghua Liu, Saritha Guntuku, Xian Shu Cui, Shuhei Matsuoka, David Cortez, Katsuyuki Tamai, Guangbin Luo, Sandra Carattini-Rivera, Francisco DeMayo, Allan Bradley, Larry A. Donehower, Stephen J. Elledge

Research output: Contribution to journalArticle

1285 Scopus citations

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 languageEnglish (US)
Pages (from-to)1448-1459
Number of pages12
JournalGenes and Development
Volume14
Issue number12
StatePublished - Jun 15 2000

Keywords

  • Atm
  • Atr
  • Checkpoint
  • Chk1
  • DNA damage
  • Embryonic lethality

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Liu, Q., Guntuku, S., Cui, X. S., Matsuoka, S., Cortez, D., Tamai, K., Luo, G., Carattini-Rivera, S., DeMayo, F., Bradley, A., Donehower, L. A., & Elledge, S. J. (2000). Chk1 is an essential kinase that is regulated by Atr and required for the G2/M DNA damage checkpoint. Genes and Development, 14(12), 1448-1459.