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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
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
Mitotic Phosphorylation of Histone H3: Spatio-Temporal Regulation by Mammalian Aurora Kinases
Crosio, C., Fimia, G. M., Loury, R., Kimura, M., Okano, Y., Zhou, H., Sen, S., Allis, C. D., & Sassone‐Corsi, P. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.3.874-885.2002 · Cited by 668
Mammalian G1- and S-phase checkpoints in response to DNA damage
Bártek, J., & Lukas, J. (2001) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00280-5 · Cited by 573
Involvement of Brca1 in S-Phase and G 2 -Phase Checkpoints after Ionizing Irradiation
Xu, B., Kim, S., & Kastan, M. B. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.10.3445-3450.2001 · Cited by 550
The base excision repair pathway
Seeberg, E., Eide, L., & Bjørås, M. (1995) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(00)89086-6 · Cited by 542
Graves, P. R., Yu, L., Schwarz, J. K., Gales, J., Sausville, E. A., O'Connor, P. M., & Piwnica-Worms, H. M. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.8.5600 · Cited by 540
DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme?
Durocher, D., & Jackson, S. P. (2001) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00201-5 · Cited by 523
Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance
Brown, E. J., & Baltimore, D. (2003) · Genes & Development · doi:10.1101/gad.1067403 · Cited by 511
Hoffmann, I., Draetta, G. F., & Karsenti, E. (1994) · The EMBO Journal · doi:10.1002/j.1460-2075.1994.tb06750.x · Cited by 495
Zhao, H., Watkins, J. L., & Piwnica-Worms, H. M. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182557299 · Cited by 472
Duckett, D. R., Drummond, J. T., Murchie, A. I. H., Reardon, J. T., Sancar, A., Lilley, D. M. J., & Modrich, P. L. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.13.6443 · Cited by 421
DiTullio, R. A., Mochan, T. A., Venere, M., Bártková, J., Sehested, M., Bártek, J., & Halazonetis, T. D. (2002) · Nature Cell Biology · doi:10.1038/ncb892 · Cited by 412
Role of Postreplicative DNA Mismatch Repair in the Cytotoxic Action of Thioguanine
SWANN, P. F., Waters, T. R., Moulton, D. C., Xu, Y., Zheng, Q., Edwards, M., & Mace, R. (1996) · Science · doi:10.1126/science.273.5278.1109 · Cited by 409
Evidence for a connection between the mismatch repair system and the G2 cell cycle checkpoint.
Hawn, M. T., Umar, A., Carethers, J. M., Marra, G., Kunkel, T. A., Boland, C. R., & Koi, M. (1995) · PubMed · Cited by 360
Self-citationChecking on the fork: the DNA-replication stress-response pathway
Osborn, A. J., Elledge, S. J., & Zou, L. (2002) · Trends in Cell Biology · doi:10.1016/s0962-8924(02)02380-2 · Cited by 347
Jeggo, P. A., & Kemp, L. M. (1983) · Mutation Research/DNA Repair Reports · doi:10.1016/0167-8817(83)90026-3 · Cited by 337
Regulation of G2/M events by Cdc25A through phosphorylation‐dependent modulation of its stability
Mailand, N., Podtelejnikov, A. V., Groth, A., Mann, M., Bartek, J., & Lukas, J. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf567 · Cited by 315
(2000) · PubMed · Cited by 314
Involvement of the Mismatch Repair System in Temozolomide-Induced Apoptosis
D’Atri, S., Tentori, L., Lacal, P. M., Graziani, G., Pagani, E., Benincasa, E., Zambruno, G., Bonmassar, E., & Jiricny, J. (1998) · Molecular Pharmacology · doi:10.1124/mol.54.2.334 · Cited by 282
Self-citationZhou, B. S., Chaturvedi, P., Spring, K. J., Scott, S. P., Johanson, R. A., Mishra, R., Mattern, M. R., Winkler, J. D., & Khanna, K. K. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.14.10342 · Cited by 278
hMSH3 and hMSH6 interact with PCNA and colocalize with it to replication fociPreprint
Kleczkowska, H. E., Marra, G., Lettieri, T., & Jiricny, J. (2001) · Genes & Development · doi:10.1101/gad.191201 · Cited by 251
Self-citationRecombinant ATM protein complements the cellular A-T phenotype
Ziv, Y., Bar‐Shira, A., Pecker, I., Russell, P. S., Jorgensen, T. J., Tsarfati, I., & Shiloh, Y. (1997) · Oncogene · doi:10.1038/sj.onc.1201319 · Cited by 240
Mechanisms of tolerance to DNA damaging therapeutic drugs
Karran, P. (2001) · Carcinogenesis · doi:10.1093/carcin/22.12.1931 · Cited by 226
Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system
Trojan, J., Zeuzem, S., Randolph, A. E., Hemmerle, C., Brieger, A., Raedle, J., Plotz, G., Jiricny, J., & Marra, G. (2002) · Gastroenterology · doi:10.1053/gast.2002.30296 · Cited by 213
Self-citationS Phase and G2 Arrests Induced by Topoisomerase I Poisons Are Dependent on ATR Kinase Function
Cliby, W. A., Lewis, K. A., Lilly, K. K., & Kaufmann, S. H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m106287200 · Cited by 205
Kaina, B., Ziouta, A., Ochs, K., & Coquerelle, T. M. (1997) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/s0027-5107(97)00187-5 · Cited by 197
Methylation‐induced G2/M arrest requires a full complement of the mismatch repair protein hMLH1
Ćejka, P., Stojic, L., Mojaš, N., Russell, A., Heinimann, K., Cannavò, E., di Pietro, M., Marra, G., & Jiricny, J. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg216 · Cited by 195
Self-citationUmar, A., Koi, M., Risinger, J. I., Glaab, W. E., Tindall, K. R., Kolodner, R. D., Boland, C. R., Barrett, J. C., & Kunkel, T. A. (1997) · PubMed · Cited by 193
Functional interactions and signaling properties of mammalian DNA mismatch repair proteins
Bellacosa, A. (2001) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400948 · Cited by 191
Mismatch repair, molecular switches, and signal transductionPreprint
Fishel, R. A. (1998) · Genes & Development · doi:10.1101/gad.12.14.2096 · Cited by 177
Self-destruction and tolerance in resistance of mammalian cells to alkylation damage
Karran, P., & Bignami, M. (1992) · Nucleic Acids Research · doi:10.1093/nar/20.12.2933 · Cited by 175
A public domain image-analysis program for the single-cell gel-electrophoresis (comet) assay
Helma, C., & Uhl, M. (2000) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/s1383-5718(99)00232-6 · Cited by 173
Anterior pituitary hormones, stress, and immune system homeostasis
Dorshkind, K. A., & Horseman, N. D. (2001) · BioEssays · doi:10.1002/1521-1878(200103)23:3 · Cited by 157
Self-citationRecent progress on the Ada response for inducible repair of DNA alkylation damage
Sedgwick, B., & Lindahl, T. L. (2002) · Oncogene · doi:10.1038/sj.onc.1205998 · Cited by 144
Signaling mismatch repair in cancer
Fishel, R. A. (1999) · Nature Medicine · doi:10.1038/15191 · Cited by 135
Wang, H., Guan, J., Wang, H., Perrault, A. R., Wang, Y., & Iliakis, G. E. (2001) · PubMed · Cited by 123
Yan, T., Berry, S. E., Desai, A. B., & Kinsella, T. J. (2003) · PubMed · Cited by 104
ATR Is Not Required for p53 Activation but Synergizes with p53 in the Replication Checkpoint
Nghiem, P., Park, P. K., Kim, Y.-S., Desai, B. N., & Schreiber, S. L. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m106113200 · Cited by 99
Wang, X., Khadpe, J. D., Hu, B., Iliakis, G. E., & Wang, Y. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301876200 · Cited by 71
Goudelock, D. M., Jiang, K., Pereira, E., Russell, B., & Sánchez, Y. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301765200 · Cited by 69
Mismatch repair, G 2 /M cell cycle arrest and lethality after DNA damage
Aquilina, G., Crescenzi, M., & Bignami, M. (1999) · Carcinogenesis · doi:10.1093/carcin/20.12.2317 · Cited by 69
Galloway, S. M., Greenwood, S. K., Hill, R., Bradt, C. I., & Bean, C. L. (1995) · Mutation Research Letters · doi:10.1016/0165-7992(95)90040-3 · Cited by 67
Plant, J. E., & Roberts, J. J. (1971) · Chemico-Biological Interactions · doi:10.1016/0009-2797(71)90013-5 · Cited by 65
ATM Is Activated in Response toN-Methyl-N′-nitro- N-nitrosoguanidine-induced DNA Alkylation
Adamson, A. W., Kim, W.-J., Shangary, S. K., Baskaran, R., & Brown, K. D. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204409200 · Cited by 61
Methylation tolerance in mismatch repair proficient cells with low MSH2 protein level
Claij, N., & Riele, H. T. (2002) · Oncogene · doi:10.1038/sj.onc.1205395 · Cited by 55
Drug-related killings: a case of mistaken identity
Karran, P., & Bignami, M. (1996) · Chemistry & Biology · doi:10.1016/s1074-5521(96)90175-1 · Cited by 48
Processing of O6-methylguanine by mismatch correction in human cell extracts
Ceccotti, S., Aquilina, G., Macpherson, P., Yamada, M., Karran, P., & Bignami, M. (1996) · Current Biology · doi:10.1016/s0960-9822(96)00758-0 · Cited by 45
DNA replication arrest and tolerance to DNA methylation damage
Zhukovskaya, N. L., Branch, P., Aquilina, G., & Karran, P. (1994) · Carcinogenesis · doi:10.1093/carcin/15.10.2189 · Cited by 34
Replication of O6-Methylguanine-containing DNA by Repair and Replicative DNA Polymerases
Reha-Krantz, L. J., Nonay, R. L., Day, R. S., & Wilson, S. H. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.33.20088 · Cited by 33
O6-Methylguanine in DNA inhibits replication in vitro by human cell extracts
Ceccotti, S., Eugenia Dogliotti, Y., Gannon, J., Karran, P., & Bignami, M. (1993) · Biochemistry · doi:10.1021/bi00212a035 · Cited by 24
di Pietro, M., Marra, G., Ćejka, P., Stojic, L., Menigatti, M., Cattaruzza, M. S., & Jiricny, J. (2003) · PubMed · doi:10.5167/uzh-31248 · Cited by 23
Self-citationKhare, V., & Eckert, K. A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m011025200 · Cited by 15
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
Cited by
Sorted by citations
Mechanisms and functions of DNA mismatch repair
Li, G. (2007) · Cell Research · doi:10.1038/cr.2007.115 · Cited by 1,479
The multifaceted mismatch-repair system
Jiricny, J. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1907 · Cited by 1,375
Self-citationGenomic and Epigenetic Instability in Colorectal Cancer Pathogenesis
Grady, W. M., & Carethers, J. M. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.07.076 · Cited by 991
DNA Mismatch Repair: Functions and Mechanisms
Iyer, R. R., Pluciennik, A., Burdett, V., & Modrich, P. L. (2005) · Chemical Reviews · doi:10.1021/cr0404794 · Cited by 935
MGMT promoter methylation in malignant gliomas: ready for personalized medicine?
Weller, M., Stupp, R., Reifenberger, G., Brandes, A. A., van den Bent, M. J., Wick, W., & Hegi, M. E. (2009) · Nature Reviews Neurology · doi:10.1038/nrneurol.2009.197 · Cited by 803
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
