The DOI matches its Crossref record; 61 of the 61 references it cites were found in a registry or an index.
Mismatch repair-dependent G2 checkpoint induced by low doses of SN1 type methylating agents requires the ATR kinase
Open accessAbstract
S N 1-type alkylating agents represent an important class of chemotherapeutics, but the molecular mechanisms underlying their cytotoxicity are unknown. Thus, although these substances modify predominantly purine nitrogen atoms, their toxicity appears to result from the processing of O6-methylguanine (6Me G)-containing mispairs by the mismatch repair (MMR) system, because cells with defective MMR are highly resistant to killing by these agents. In an attempt to understand the role of the MMR system in the molecular transactions underlying the toxicity of alkylating agents, we studied the response of human MMR-proficient and MMR-deficient cells to low concentrations of the prototypic methylating agent N-methyl-N′-nitro-N-nitrosoguanidine (MNNG). We now show that MNNG treatment induced a cell cycle arrest that was absolutely dependent on functional MMR. Unusually, the cells arrested only in the second G 2 phase after treatment. Downstream targets of both ATM (Ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) kinases were modified, but only the ablation of ATR, or the inhibition of CHK1, attenuated the arrest. The checkpoint activation was accompanied by the formation of nuclear foci containing the signaling and repair proteins ATR, the S*/T*Q substrate, γ-H2AX, and replication protein A (RPA). The persistence of these foci implied that they may represent sites of irreparable damage.
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“MLH1 is also required for MNNG-induced ATR checkpoint activation such as Chk1 phosphorylation and the colocalization of γ-H2AX and RPA [213]”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [213]
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Cites
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
Bakkenist, C. J., & Kastan, M. B. (2003) · Nature · doi:10.1038/nature01368 · Cited by 3,466
Oxidative DNA damage: mechanisms, mutation, and disease
Cooke, M. S., Evans, M. D., Dizdaroglu, M., & Lunec, J. (2003) · The FASEB Journal · doi:10.1096/fj.02-0752rev · Cited by 3,245
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
ATM and related protein kinases: safeguarding genome integrity
Shiloh, Y. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1011 · Cited by 2,577
Megabase Chromatin Domains Involved in DNA Double-Strand Breaks in Vivo
Rogakou, E. P., Boon, C., Redon, C., & Bonner, W. M. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.146.5.905 · Cited by 2,422
A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage
Paull, T. T., Rogakou, E. P., Yamazaki, V., Kirchgessner, C. U., Gellert, M., & Bonner, W. M. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00610-2 · Cited by 2,098
Cell cycle checkpoint signaling through the ATM and ATR kinases
Abraham, R. T. (2001) · Genes & Development · doi:10.1101/gad.914401 · Cited by 1,966
Liu, Q., Guntuku, S., Cui, X.-S., Matsuoka, S., Cortez, D., Tamai, K., Luo, G., Carattini-Rivera, S., DeMayo, F., Bradley, A., et al. (2000) · Genes & Development · doi:10.1101/gad.14.12.1448 · Cited by 1,625
The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis
Falck, J., Mailand, N., Syljuåsen, R. G., Bartek, J., & Lukas, J. (2001) · Nature · doi:10.1038/35071124 · Cited by 1,085
(1999) · PubMed · Cited by 1,030
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Research works printed but not linked: 7
- 2000, Cancer Res., 60, 2108
- 2003, Cancer Res., 63, 8158
- 1995, Cancer Res., 55, 3721
- 1999, Cancer Res., 59, 4375
- 1997, Cancer Res., 57, 3949
- 2001, Cancer Res., 61, 8554
- 2003, Clin. Cancer Res., 9, 2327
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Hwang, T., Sitko, L. K., Khoirunnisa, R., Aguad, F. N., Samuel, D. M., Park, H., Cheon, B., Mutsnaini, L., Lee, J., Takeda, S., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.04.17.590003
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Shin, Y., Kim, D. K., Seo, Y., Lee, H. H., Park, J., Park, S.-J., Park, J. J., Cheon, J. H., Oh, J., Lee, S., et al. (2026) · International Journal of Cancer · doi:10.1002/ijc.70646
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Li, X., Vicinanza, M., Lopez, A., Festa, B. P., Schlotawa, L., Barbosa, A. D., Takla, M., Balmus, G., Fleming, A., & Rubinsztein, D. C. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag696
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del Campo-Balguerías, A., Ocaña, A., Bravo, I., & Alonso‐Moreno, C. (2026) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2026.110295
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Sakai, A. H., Sakalem, M. E., Rocha, L. M. O., da Silva, I. M., Silva, F. E. S., Ribeiro, D. L., Menck, C. F. M., Negreiros, H. A., Sousa, J. M. D. C. E., & Serpeloni, J. M. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1901494
Gao, H. (2006) · UA Campus Repository (The University of Arizona)
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Metadata
- Authors
- Stojic, L., Mojas, N., Cejka, P., di Pietro, M., Ferrari, S., Marra, G., & Jiricny, J.
- Affiliations
- University of Zurich (CH)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2004-06-01
- Volume
- 18
- Issue
- 11
- Pages
- 1331-1344
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC420358
- OpenAlex
- W2127970987
- Cited by
- 246
- References
- 61
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 8 · 2022: 5 · 2021: 4 · 2020: 6 · 2019: 7 · 2018: 3 · 2017: 7 · 2016: 7 · 2015: 7 · 2014: 17 · 2013: 14 · 2012: 14
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- Locations
- Genes & Development (publishedVersion, public-domain)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (064650)
- National Institutes of Health
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- DNA mismatch repair, G2 checkpoint, ATR kinase, N-methyl-N'-nitro-N-nitrosoguanidine, O6-methylguanine, cell cycle arrest, ATM kinase, Chk1, γH2AX, replication protein A, DNA repair
- MeSH terms
- Checkpoint Kinase 1, Caffeine, Cell Cycle, Cell Line, DNA, DNA Damage, DNA Repair, DNA-Binding Proteins, Dose-Response Relationship, Drug, Enzyme Inhibitors, Histones, Humans, Methylation, Methylnitronitrosoguanidine, Phosphorylation, Protein Kinases, Signal Transduction, G2 Phase, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Staurosporine, Base Pair Mismatch, Tumor Suppressor Proteins, Protein Kinase Inhibitors, Replication Protein A, Ataxia Telangiectasia Mutated Proteins
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