Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53.

By N. Chehab, Asra Malikzay, M. Appel, T. Halazonetis. Genes & Development, 2000

853 citations recorded by the source corpus.

Chk2/hcds1, the human homolog of the Saccharomyces cerevisiae RAD53/SPK1 and Schizosaccharomyces pombe cds1 DNA damage checkpoint genes, encodes a protein kinase that is post-translationally modified after DNA damage. Like its yeast homologs, the Chk2/hCds1 protein phosphorylates Cdc25C in vitro, suggesting that it arrests cells in G(2) in response to DNA damage. We expressed Chk2/hCds1 in human cells and analyzed their cell cycle profile. Wild-type, but not catalytically inactive, Chk2/hCds1 led to G(1) arrest after DNA damage. The arrest was inhibited by cotransfection of a dominant-negative p53 mutant, indicating that Chk2/hCds1 acted upstream of p53. In vitro, Chk2/hCds1 phosphorylated p53 on Ser-20 and dissociated preformed complexes of p53 with Mdm2, a protein that targets p53 for degradation. In vivo, ectopic expression of wild-type Chk2/hCds1 led to increased p53 stabilization after DNA damage, whereas expression of a dominant-negative Chk2/hCds1 mutant abrogated both phosphorylation of p53 on Ser-20 and p53 stabilization. Thus, in response to DNA damage, Chk2/hCds1 stabilizes the p53 tumor suppressor protein leading to cell cycle arrest in G(1).

Subfields: Cell Biology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/24d7ee1d72bc8b8ecb6d6af14008e1072ddceb76

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In Cell Biology

1. B. Kaina
2. R. Abraham
3. W. Roos
4. T. Halazonetis
5. J. Bartek

In Molecular Biology

1. R. Abraham
2. T. Halazonetis
3. B. Kaina
4. W. Roos
5. Carol Prives
6. Moshe Oren
7. M. Tomicic
8. M. Christmann

In Oncology

1. R. Abraham
2. T. Halazonetis
3. B. Kaina
4. W. Roos
5. Carol Prives
6. Moshe Oren
7. M. Tomicic
8. M. Christmann

Citations in the corpus

• P53 Binding Protein 1 (53bp1) Is an Early Participant in the Cellular Response to DNA Double-Strand Breaks (2000, methodology): “…kinase (Matsuoka et al., 1998; Blasina et al., 1999a; Brown et al., 1999; Chaturvedi et al., 1999), which in turn targets the p53 tumor suppressor protein and other proteins regulating cell cycle progression, such as Cdc25c (Matsuoka et al., 1998; Chehab et al., 2000; Hirao et al., 2000).”
• USP10 Regulates p53 Localization and Stability by Deubiquitinating p53 (2010, neutral): “For example, p53 is phosphorylated at Ser20 by the checkpoint kinase Chk2 after IR, which results in p53’s dissociation from Mdm2 and its subsequent stabilization (Chehab et al., 2000; Hirao et al., 2000; Shieh et al., 2000).”
• Mechanisms of human DNA repair: an update. (2003, background): “…Chk1 are able to phosphorylate p53 at Ser20 (Shieh et al., 2000), giving rise to blockage of the MDM2-binding site-thus leading to release of p53 from MDM2-a protein that normally targets p53 for ubiquitin-dependent degradation (Chehab et al., 1999, 2000; Hirao et al., 2000; Unger et al., 1999).”
• Cell cycle checkpoint signaling through the ATM and ATR kinases. (2001, background): “ATM activates hChk2 by phosphorylating an amino terminal Thr residue (Thr 68) (Ahn et al. 2000; Melchionna et al. 2000), and hChk2, in turn, phosphorylates yet another amino-terminal Ser residue (Ser 20) in p53 (Chehab et al. 2000; Hirao et al. 2000; Shieh et al. 2000).”
• DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis. (2013, background): “nation of p53 by the ubiquitin E3 ligase MDM2 and prevents its proteosomal degradation and the p53 protein is stabilized [117].”