ATR-Mediated Checkpoint Pathways Regulate Phosphorylation and Activation of Human Chk1

Zhao, Hui; Piwnica-Worms, Helen

doi:10.1128/mcb.21.13.4129-4139.2001

Cited by 1,091DNA Repair MechanismsCancer-related Molecular PathwaysProtein Kinase Regulation and GTPase Signaling

ATR-Mediated Checkpoint Pathways Regulate Phosphorylation and Activation of Human Chk1

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Zhao, Hui, Piwnica-Worms, Helen·2001·Molecular and Cellular Biology

DOI 10.1128/mcb.21.13.4129-4139.2001PMC PMC87074

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Abstract

Chk1 is an evolutionarily conserved protein kinase that regulates cell cycle progression in response to checkpoint activation. In this study, we demonstrated that agents that block DNA replication or cause certain forms of DNA damage induce the phosphorylation of human Chk1. The phosphorylated form of Chk1 possessed higher intrinsic protein kinase activity and eluted more quickly on gel filtration columns. Serines 317 and 345 were identified as sites of phosphorylation in vivo, and ATR (the ATM- and Rad3-related protein kinase) phosphorylated both of these sites in vitro. Furthermore, phosphorylation of Chk1 on serines 317 and 345 in vivo was ATR dependent. Mutants of Chk1 containing alanine in place of serines 317 and 345 were poorly activated in response to replication blocks or genotoxic stress in vivo, were poorly phosphorylated by ATR in vitro, and were not found in faster-eluting fractions by gel filtration. These findings demonstrate that the activation of Chk1 in response to replication blocks and certain forms of genotoxic stress involves phosphorylation of serines 317 and 345. In addition, this study implicates ATR as a direct upstream activator of Chk1 in human cells.

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Chk1 is phosphorylated at serine 345 by ATR in response to stalled DNA replication forks and DNA damage induced by UV, ionizing radiation, methyl methanesulfonate, mitomycin C, and hydrogen peroxide.
“As a critical player in DDR, Chk1 is phosphorylated at Serine 345 by ATR in response to stalled DNA replication forks and DNA damage induced by UV, IR, methyl methanesulfonate (MMS), mitomycin C (MMC), and hydrogen peroxide [85–90].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [87]

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“Consistent with the absence DNA breaks, RPA32 protein, which is an activator and an early target of the primary CHK1 kinase ATR in the presence of single strand DNA regions [19, 20], was not phosphorylated in Spi1-overexpressing pre-leukemic cells, nor was it phosphorylated in cells with reduced Spi1 expression (treat…”
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Authors: Zhao, H., & Piwnica-Worms, H.
Affiliations: Washington University in St. Louis (US)
Howard Hughes Medical Institute (US)
ORCID: Zhao, Hui
Piwnica-Worms, Helen
Venue: Molecular and Cellular Biology
Publisher: Informa UK Limited
Published: 2001-07-01
Volume: 21
Issue: 13
Pages: 4129-4139
ISSN: 0270-7306 (ISSN-L)
1098-5549
DOI: 10.1128/mcb.21.13.4129-4139.2001
PMC: PMC87074
OpenAlex: W2111403239
Cited by: 1,091
References: 77
Citations by year: 2026: 22 · 2025: 24 · 2024: 22 · 2023: 44 · 2022: 24 · 2021: 45 · 2020: 55 · 2019: 30 · 2018: 36 · 2017: 43 · 2016: 30 · 2015: 46 · 2014: 55 · 2013: 53 · 2012: 45
FWCI: 16.21
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Molecular and Cellular Biology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Howard Hughes Medical Institute
National Institutes of Health
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 › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: Chk1, ATR kinase, DNA damage checkpoint, DNA replication checkpoint, serine phosphorylation, protein kinase activation, genotoxic stress, replication block, cell cycle regulation, checkpoint signaling
MeSH terms: Checkpoint Kinase 1, Adenoviridae, Antineoplastic Agents, Caffeine, Cell Cycle, Cell Line, Cisplatin, Cytarabine, DNA Damage, Enzyme Activation, Etoposide, Humans, Hydroxyurea, Phosphodiesterase Inhibitors, Phosphoric Monoester Hydrolases, Phosphorylation, Phosphoserine, Protein Kinases, Recombinant Fusion Proteins, Immunoblotting, Protein Serine-Threonine Kinases, Genes, Reporter, Cell Cycle Proteins, Nucleic Acid Synthesis Inhibitors, Amino Acid Motifs, Ataxia Telangiectasia Mutated Proteins

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ATR-Mediated Checkpoint Pathways Regulate Phosphorylation and Activation of Human Chk1

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