Document Detail


Methylator-induced, mismatch repair-dependent G2 arrest is activated through Chk1 and Chk2.
MedLine Citation:
PMID:  15647386     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
SN1 DNA methylating agents such as the nitrosourea N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) elicit a G2/M checkpoint response via a mismatch repair (MMR) system-dependent mechanism; however, the exact nature of the mechanism governing MNNG-induced G2/M arrest and how MMR mechanistically participates in this process are unknown. Here, we show that MNNG exposure results in activation of the cell cycle checkpoint kinases ATM, Chk1, and Chk2, each of which has been implicated in the triggering of the G2/M checkpoint response. We document that MNNG induces a robust, dose-dependent G2 arrest in MMR and ATM-proficient cells, whereas this response is abrogated in MMR-deficient cells and attenuated in ATM-deficient cells treated with moderate doses of MNNG. Pharmacological and RNA interference approaches indicated that Chk1 and Chk2 are both required components for normal MNNG-induced G2 arrest. MNNG-induced nuclear exclusion of the cell cycle regulatory phosphatase Cdc25C occurred in an MMR-dependent manner and was compromised in cells lacking ATM. Finally, both Chk1 and Chk2 interact with the MMR protein MSH2, and this interaction is enhanced after MNNG exposure, supporting the notion that the MMR system functions as a molecular scaffold at the sites of DNA damage that facilitates activation of these kinases.
Authors:
Aaron W Adamson; Dillon I Beardsley; Wan-Ju Kim; Yajuan Gao; R Baskaran; Kevin D Brown
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2005-01-12
Journal Detail:
Title:  Molecular biology of the cell     Volume:  16     ISSN:  1059-1524     ISO Abbreviation:  Mol. Biol. Cell     Publication Date:  2005 Mar 
Date Detail:
Created Date:  2005-02-25     Completed Date:  2005-08-16     Revised Date:  2013-05-24    
Medline Journal Info:
Nlm Unique ID:  9201390     Medline TA:  Mol Biol Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1513-26     Citation Subset:  IM    
Affiliation:
Department of Biochemistry and Molecular Biology and the Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
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MeSH Terms
Descriptor/Qualifier:
Base Pair Mismatch*
Cell Division
Cell Nucleus / metabolism
Cells, Cultured
DNA Damage
DNA Methylation
DNA Repair*
DNA-Binding Proteins / metabolism,  physiology*
Dose-Response Relationship, Drug
Electrophoresis, Polyacrylamide Gel
Flow Cytometry
G2 Phase*
Humans
Immunoblotting
Immunoprecipitation
Methylnitronitrosoguanidine / pharmacology
MutS Homolog 2 Protein
Protein Kinase Inhibitors / pharmacology
Protein Kinases / genetics,  physiology*
Protein-Serine-Threonine Kinases / genetics,  physiology*
Proto-Oncogene Proteins / metabolism,  physiology*
RNA Interference
RNA, Small Interfering / metabolism
Staurosporine / analogs & derivatives*,  pharmacology
Subcellular Fractions
Time Factors
Grant Support
ID/Acronym/Agency:
R01-CA102289/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Protein Kinase Inhibitors; 0/Proto-Oncogene Proteins; 0/RNA, Small Interfering; 62996-74-1/Staurosporine; 70-25-7/Methylnitronitrosoguanidine; 7BU5H4V94A/7-hydroxystaurosporine; EC 2.7.-/Protein Kinases; EC 2.7.1.11/checkpoint kinase 2; EC 2.7.11.1/Checkpoint kinase 1; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 3.6.1.3/MSH2 protein, human; EC 3.6.1.3/MutS Homolog 2 Protein
Comments/Corrections

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