The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
Inhibition of Human Chk1 Causes Increased Initiation of DNA Replication, Phosphorylation of ATR Targets, and DNA Breakage
Open accessAbstract
Human checkpoint kinase 1 (Chk1) is an essential kinase required to preserve genome stability. Here, we show that Chk1 inhibition by two distinct drugs, UCN-01 and CEP-3891, or by Chk1 small interfering RNA (siRNA) leads to phosphorylation of ATR targets. Chk1-inhibition triggered rapid, pan-nuclear phosphorylation of histone H2AX, p53, Smc1, replication protein A, and Chk1 itself in human S-phase cells. These phosphorylations were inhibited by ATR siRNA and caffeine, but they occurred independently of ATM. Chk1 inhibition also caused an increased initiation of DNA replication, which was accompanied by increased amounts of nonextractable RPA protein, formation of single-stranded DNA, and induction of DNA strand breaks. Moreover, these responses were prevented by siRNA-mediated downregulation of Cdk2 or the replication initiation protein Cdc45, or by addition of the CDK inhibitor roscovitine. We propose that Chk1 is required during normal S phase to avoid aberrantly increased initiation of DNA replication, thereby protecting against DNA breakage. These results may help explain why Chk1 is an essential kinase and should be taken into account when drugs to inhibit this kinase are considered for use in cancer treatment.
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Cites
The DNA damage response: putting checkpoints in perspective
Zhou, B.-B. S., & Elledge, S. J. (2000) · Nature · doi:10.1038/35044005 · Cited by 3,213
Sensing DNA Damage Through ATRIP Recognition of RPA-ssDNA Complexes
Zou, L., & Elledge, S. J. (2003) · Science · doi:10.1126/science.1083430 · Cited by 2,693
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ATR-Mediated Checkpoint Pathways Regulate Phosphorylation and Activation of Human Chk1
Zhao, H., & Piwnica-Worms, H. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.13.4129-4139.2001 · Cited by 1,091
A role for ATR in the DNA damage-induced phosphorylation of p53
Tibbetts, R. S., Brumbaugh, K. M., Williams, J. M., Sarkaria, J. N., Cliby, W. A., Shieh, S.-Y., Taya, Y., Prives, C., & Abraham, R. T. (1999) · Genes & Development · doi:10.1101/gad.13.2.152 · Cited by 1,046
ATR disruption leads to chromosomal fragmentation and early embryonic lethality
Brown, E. J., & Baltimore, D. (2000) · Genes & Development · doi:10.1101/gad.14.4.397 · Cited by 951
Rapid Destruction of Human Cdc25A in Response to DNA Damage
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Self-citationEssential and dispensable roles of ATR in cell cycle arrest and genome maintenance
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DNA repair pathways as targets for cancer therapy
Helleday, T., Petermann, E., Lundin, C., Hodgson, B., & Sharma, R. A. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2342 · Cited by 1,666
Self-citationDNA double-strand break repair: From mechanistic understanding to cancer treatment
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Self-citationDNA replication origin activation in space and time
Fragkos, M., Ganier, O., Coulombe, P., & Méchali, M. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm4002 · Cited by 543
Ibarra, A., Schwob, E., & Méndez, J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803978105 · Cited by 503
Roles of Chk1 in cell biology and cancer therapy
Zhang, Y., & Hunter, T. (2014) · International Journal of Cancer · doi:10.1002/ijc.28226 · Cited by 462
Metadata
- Authors
- Syljuåsen, R. G., Sørensen, C. S., Hansen, L. T., Fugger, K., Lundin, C., Johansson, F., Helleday, T., Sehested, M., Lukas, J., & Bartek, J.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2005-05-01
- Volume
- 25
- Issue
- 9
- Pages
- 3553-3562
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2116964110
- Cited by
- 550
- References
- 9
- FWCI
- 10.72
- Type
- journal article
- Language
- en
- Open access
- green
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- Syljuåsen, R. G., Sørensen, C. S., Hansen, L. T., Fugger, K., Lundin, C., Johansson, F., Helleday, T., Sehested, M., Lukas, J., & Bartek, J. (2005). Inhibition of Human Chk1 Causes Increased Initiation of DNA Replication, Phosphorylation of ATR Targets, and DNA Breakage. Molecular and Cellular Biology. https://doi.org/10.1128/mcb.25.9.3553-3562.2005
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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