Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint.

By Qinghua Liu, Saritha Guntuku, X. Cui, S. Matsuoka, D. Cortez, K. Tamai, G. Luo, Sandra Carattini-Rivera, F. Demayo, A. Bradley and 2 more. Genes & Development, 2000

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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 G(2)/M DNA damage checkpoint in response to gamma-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.

Subfields: Cell Biology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/be4464b9178bc82812f85abcd8c7c0b3072778a1

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Citations in the corpus

Cell cycle checkpoint signaling through the ATM and ATR kinases. (2001, background): “Similarly, overexpression of a kinase-inactive ATRKI mutant inhibited DNA damage-induced hChk1 phosphorylation in a human fibroblast cell line (Liu et al. 2000).”
DNA double-strand breaks: signaling, repair and the cancer connection (2001, background): “Studies of embryonic stem cells expressing Chek1 conditionally have shown that Chk1 is required for preventing premature mitotic entry following IR (ref”
Mechanisms of human DNA repair: an update. (2003, background): “ATM phosphorylates Chk2 (Matsuoka et al., 2000; Zhou et al., 2000) at Thr 68, whereas ATR targets Chk1 by phosphorylation at Ser345 (Guo et al., 2000; Liu et al., 2000).”
Checking on DNA damage in S phase (2004, background): “Both ATR and CHK1 have consistently been found to be essential for mammalian developmen”
Inhibiting NF-κB Activation by Small Molecules As a Therapeutic Strategy (2010, neutral): “Hence, inhibiting IκBα phosphorylation ultimately inhibits NF-κB’s transcriptional activity [29,30].”
The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair (2005, background): “The checkpoint kinase Chk1 is a central regulator of cell-cycle delays in S and G2 phases of the cell cycl”
Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. (2005, background): “This residue is phosphorylated in an ATRdependent manner following UV and aphidicolin treatment (Guo et al. 2000; Hekmat-Nejad et al. 2000; Liu et al. 2000).”
Cellular response to hyperosmotic stresses. (2007, background): “Phosphorylation of Chk1 is important for the cell cycle arrest induced by the DNA damage from other stresses (173), but high NaCl does not cause phosphorylation of Chk1 and, in fact, prevents its phosphorylation in response to DNA damage caused by UV or IR (73).”