PreprintCited by 246DNA Repair MechanismsGenetic factors in colorectal cancerChromatin Remodeling and Cancer

Mismatch repair-dependent G2 checkpoint induced by low doses of SN1 type methylating agents requires the ATR kinase

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Stojic, Lovorka, Mojas, Nina, Cejka, Petr, di Pietro, Massimiliano, Ferrari, Stefano, Marra, Giancarlo, Jiricny, Josef·2004·Genes & Development

Abstract

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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  1. Zhao, H., Watkins, J.L., and Piwnica-Worms, H. 2002. Disrup- tion of the checkpoint kinase 1/cell division cycle 25A path- way abrogates ionizing radiation-induced S and G2 check- points. Proc. Natl. Acad. Sci. 99: 14795-14800.

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Authors
Stojic, L., Mojas, N., Cejka, P., di Pietro, M., Ferrari, S., Marra, G., & Jiricny, J.
Affiliations
University of Zurich (CH)
Venue
Genes & Development
Published
2004-06-01
Volume
18
Issue
11
Pages
1331-1344
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
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
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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