Cited by 1,320DNA Repair MechanismsCancer-related Molecular PathwaysMicrotubule and mitosis dynamics

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Conservation of the Chk1 Checkpoint Pathway in Mammals: Linkage of DNA Damage to Cdk Regulation Through Cdc25

Sanchez, Yolanda, Wong, Calvin, Thoma, Richard S., Richman, Ron, Wu, Zhiqi, Piwnica-Worms, Helen, Elledge, Stephen J.·1997·Science

DOI 10.1126/science.277.5331.1497

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Abstract

In response to DNA damage, mammalian cells prevent cell cycle progression through the control of critical cell cycle regulators. A human gene was identified that encodes the protein Chk1, a homolog of the Schizosaccharomyces pombe Chk1 protein kinase, which is required for the DNA damage checkpoint. Human Chk1 protein was modified in response to DNA damage. In vitro Chk1 bound to and phosphorylated the dual-specificity protein phosphatases Cdc25A, Cdc25B, and Cdc25C, which control cell cycle transitions by dephosphorylating cyclin-dependent kinases. Chk1 phosphorylates Cdc25C on serine-216. As shown in an accompanying paper by Peng et al . in this issue, serine-216 phosphorylation creates a binding site for 14-3-3 protein and inhibits function of the phosphatase. These results suggest a model whereby in response to DNA damage, Chk1 phosphorylates and inhibits Cdc25C, thus preventing activation of the Cdc2–cyclin B complex and mitotic entry.

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Authors: Sanchez, Y., Wong, C., Thoma, R. S., Richman, R., Wu, Z., Piwnica-Worms, H., & Elledge, S. J.
Affiliations: Y. Sanchez, C. Wong, S. J. Elledge, Verna and Marrs McLean Department of Biochemistry, Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Howard Hughes Medical Institute (US)
ORCID: Wu, Zhiqi
Piwnica-Worms, Helen
Elledge, Stephen J.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 1997-09-05
Volume: 277
Issue: 5331
Pages: 1497-1501
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.277.5331.1497
OpenAlex: W2105592350
Cited by: 1,320
References: 24
Citations by year: 2026: 11 · 2025: 20 · 2024: 14 · 2023: 32 · 2022: 29 · 2021: 25 · 2020: 30 · 2019: 22 · 2018: 22 · 2017: 35 · 2016: 34 · 2015: 39 · 2014: 29 · 2013: 37 · 2012: 39
FWCI: 30.74
Type: journal article
Language: en
Open access: closed
Locations: Science (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (1f32gm017763-01)
National Institute of General Medical Sciences (GM-44664, GM17763)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
Keywords: Chk1, DNA damage checkpoint, Cdc25 phosphatase, cyclin-dependent kinases, cell cycle regulation, 14-3-3 protein binding, mitotic entry, protein kinases, mammalian cells
MeSH terms: Checkpoint Kinase 1, F-Box-WD Repeat-Containing Protein 7, Amino Acid Sequence, Animals, Chromosome Mapping, Chromosomes, Human, Pair 11, Cytoskeletal Proteins, DNA Damage, HeLa Cells, Humans, Mitosis, Molecular Sequence Data, Phosphoprotein Phosphatases, Phosphorylation, Phosphoserine, Protein Kinases, Proteins, Recombinant Fusion Proteins, Transfection, Tyrosine 3-Monooxygenase, Signal Transduction, G2 Phase, CDC2 Protein Kinase, Protein Tyrosine Phosphatases, Cell Cycle Proteins, cdc25 Phosphatases, Schizosaccharomyces pombe Proteins, Ubiquitin-Protein Ligases, F-Box Proteins, 14-3-3 Proteins, Mice

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Conservation of the Chk1 Checkpoint Pathway in Mammals: Linkage of DNA Damage to Cdk Regulation Through Cdc25

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