Document Detail


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.
MedLine Citation:
PMID:  22892544     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Ericka M Noonan; Dharini Shah; Michael B Yaffe; Douglas A Lauffenburger; Leona D Samson
Related Documents :
20813254 - A new spin on planar cell polarity.
19424014 - Memory t cells: how might they disrupt the induction of tolerance?
9655804 - Leafbladeless1 is required for dorsoventrality of lateral organs in maize.
22348144 - The translation factor eif6 is a notch-dependent regulator of cell migration and invasion.
17314394 - Epigenetic reprogramming of oct4 and nanog regulatory regions by embryonal carcinoma ce...
20576604 - Myosin vi is differentially regulated by dna damage in p53- and cell type-dependent man...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
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:
Created Date:  2012-09-24     Completed Date:  2013-02-13     Revised Date:  2014-09-24    
Medline Journal Info:
Nlm Unique ID:  101478378     Medline TA:  Integr Biol (Camb)     Country:  England    
Other Details:
Languages:  eng     Pagination:  1237-55     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / 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:
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; U54 CA112967/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 20535-83-5/O-(6)-methylguanine; 5Z93L87A1R/Guanine; 9007-49-2/DNA
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Recent developments in copper-catalyzed reactions of diazo compounds.
Next Document:  Application of Dempster-Shafer theory in dose response outcome analysis.