| O6-Methylguanine DNA lesions induce an intra-S-phase arrest from which cells exit into apoptosis governed by early and late multi-pathway signaling network activation. | |
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MedLine Citation:
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PMID: 22892544 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The O(6)-methylguanine (O(6)MeG) DNA lesion is well known for its mutagenic, carcinogenic, and cytotoxic properties, and understanding how a cell processes such damage is of critical importance for improving current cancer therapy. Here we use human cells differing only in their O(6)MeG DNA methyltransferase (MGMT) or mismatch repair (MMR) status to explore the O(6)MeG/MMR-dependent molecular and cellular responses to treatment with the methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). We find that O(6)MeG triggers MMR-dependent cell cycle perturbations in both the first and second cell cycle post treatment. At lower levels of damage, we show that a transient arrest in the second S-phase precedes survival and progression into subsequent cell cycles. However, at higher levels of damage, arrest in the second S-phase coincides with a cessation of DNA replication followed by initiation of apoptotic cell death. Further, we show that entry into apoptotic cell death is specifically from S-phase of the second cell cycle. Finally, we demonstrate the key role of an O(6)MeG/MMR-dependent multi-pathway, multi-time-scale signaling network activation, led by early ATM, H2AX, CHK1, and p53 phosphorylation and followed by greatly amplified late phosphorylation of the early pathway nodes along with activation of the CHK2 kinase and the stress-activated JNK kinase. |
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Authors:
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Ericka M Noonan; Dharini Shah; Michael B Yaffe; Douglas A Lauffenburger; Leona D Samson |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Integrative biology : quantitative biosciences from nano to macro Volume: 4 ISSN: 1757-9708 ISO Abbreviation: Integr Biol (Camb) Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-09-24 Completed Date: 2013-02-13 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 101478378 Medline TA: Integr Biol (Camb) Country: England |
Other Details:
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Languages: eng Pagination: 1237-55 Citation Subset: IM |
Affiliation:
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Biological Engineering Department, Biology Department, Center for Environmental Health Sciences, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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pharmacology* Apoptosis* Base Pair Mismatch Cell Cycle Cell Death Cell Line DNA / drug effects*, metabolism DNA Damage DNA Repair DNA Replication Dose-Response Relationship, Drug Gene Expression Regulation, Neoplastic Guanine / analogs & derivatives*, pharmacology Humans Neoplasms / drug therapy* S Phase Signal Transduction |
| Grant Support | |
ID/Acronym/Agency:
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CA014051/CA/NCI NIH HHS; CA055042/CA/NCI NIH HHS; CA112967/CA/NCI NIH HHS; ES002109/ES/NIEHS NIH HHS; P30 ES002109/ES/NIEHS NIH HHS; R01 CA055042/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 20535-83-5/O-(6)-methylguanine; 73-40-5/Guanine; 9007-49-2/DNA |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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