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Cited by 251DNA Repair MechanismsCancer-related Molecular PathwaysEffects of Radiation Exposure

An ATR- and Chk1-Dependent S Checkpoint Inhibits Replicon Initiation following UVC-Induced DNA Damage

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Heffernan, Timothy P., Simpson, Dennis A., Frank, Alexandra R., Heinloth, Alexandra N., Paules, Richard S., Cordeiro-Stone, Marila, Kaufmann, William K.·2002·Molecular and Cellular Biology
DOI 10.1128/mcb.22.24.8552-8561.2002PMC PMC139882
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Abstract

Inhibition of replicon initiation is a stereotypic DNA damage response mediated through S checkpoint mechanisms not yet fully understood. Studies were undertaken to elucidate the function of checkpoint proteins in the inhibition of replicon initiation following irradiation with 254 nm UV light (UVC) of diploid human fibroblasts immortalized by the ectopic expression of telomerase. Velocity sedimentation analysis of nascent DNA molecules revealed a 50% inhibition of replicon initiation when normal human fibroblasts were treated with a low dose of UVC (1 J/m(2)). Ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS), and AT-like disorder fibroblasts, which lack an S checkpoint response when exposed to ionizing radiation, responded normally when exposed to UVC and inhibited replicon initiation. Pretreatment of normal and AT fibroblasts with caffeine or UCN-01, inhibitors of ATR (AT mutated and Rad3 related) and Chk1, respectively, abolished the S checkpoint response to UVC. Moreover, overexpression of kinase-inactive ATR in U2OS cells severely attenuated UVC-induced Chk1 phosphorylation and reversed the UVC-induced inhibition of replicon initiation, as did overexpression of kinase-inactive Chk1. Taken together, these data suggest that the UVC-induced S checkpoint response of inhibition of replicon initiation is mediated by ATR signaling through Chk-1 and is independent of ATM, Nbs1, and Mre11.

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Authors
Heffernan, T. P., Simpson, D. A., Frank, A. R., Heinloth, A. N., Paules, R. S., Cordeiro-Stone, M., & Kaufmann, W. K.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • National Institutes of Health (US)
  • Department of Pathology and Laboratory Medicine, Center for Environmental Health and Susceptibility, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599
Corresponding author
Kaufmann, William K.
ORCID
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2002-12-01
Volume
22
Issue
24
Pages
8552-8561
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1128/mcb.22.24.8552-8561.2002
PMC
PMC139882
OpenAlex
W2115655831
Cited by
251
References
70
Citations by year
2025: 1 · 2024: 5 · 2023: 7 · 2022: 4 · 2021: 8 · 2020: 8 · 2019: 6 · 2018: 5 · 2017: 7 · 2016: 9 · 2015: 11 · 2014: 11 · 2013: 12 · 2012: 8
FWCI
7.07
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • UNC Libraries
Funders
  • Memorial Sloan-Kettering Cancer Center
  • Harvard University
  • National Cancer Institute (R01CA055065, P30CA 16086, CA-160-86, CA 55065, CA 81343, R01CA081343, P30CA016086)
  • National Institute of Environmental Health Sciences (P30ES10126), R01ES011012, T32ES007017, P30ES010126)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
Keywords
ATR kinase, Chk1 phosphorylation, replicon initiation, UVC-induced DNA damage, DNA damage response, ataxia telangiectasia, Nijmegen breakage syndrome, caffeine, UCN-01, NBS1, MRE11
MeSH terms
Checkpoint Kinase 1, Caffeine, Cell Line, DNA, DNA Damage, DNA Repair, DNA Replication, DNA-Binding Proteins, Doxycycline, Endodeoxyribonucleases, Enzyme Activation, Exodeoxyribonucleases, Fibroblasts, Humans, Nuclear Proteins, Phenotype, Protein Kinases, Replicon, Ultraviolet Rays, Signal Transduction, S Phase, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Genes, cdc, Telomerase, Tumor Suppressor Proteins, Saccharomyces cerevisiae Proteins, Ataxia Telangiectasia Mutated Proteins

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