Document Detail


Brca2/Xrcc2 dependent HR, but not NHEJ, is required for protection against O(6)-methylguanine triggered apoptosis, DSBs and chromosomal aberrations by a process leading to SCEs.
MedLine Citation:
PMID:  18840549     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
O(6)-methylguanine (O(6)MeG) is a highly critical DNA adduct induced by methylating carcinogens and anticancer drugs such as temozolomide, streptozotocine, procarbazine and dacarbazine. Induction of cell death by O(6)MeG lesions requires mismatch repair (MMR) and cell proliferation and is thought to be dependent on the formation of DNA double-strand breaks (DSBs) or, according to an alternative hypothesis, direct signaling by the MMR complex. Given a role for DSBs in this process, either homologous recombination (HR) or non-homologous end joining (NHEJ) or both might protect against O(6)MeG. Here, we compared the response of cells mutated in HR and NHEJ proteins to temozolomide and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The data show that cells defective in HR (Xrcc2 and Brca2 mutants) are extremely sensitive to cell death by apoptosis and chromosomal aberration formation and less sensitive to sister-chromatid exchange (SCE) induction than the corresponding wild-type. Cells defective in NHEJ were not (Ku80 mutant), or only slightly more sensitive (DNA-PK(cs) mutant) to cell death and showed similar aberration and SCE frequencies than the corresponding wild-type. Transfection of O(6)-methylguanine-DNA methyltransferase (MGMT) in all of the mutants almost completely abrogated the genotoxic effects in both HR and NHEJ defective cells, indicating the mutant-specific hypersensitivity was due to O(6)MeG lesions. MNNG provoked H2AX phosphorylation 24-48h after methylation both in wild-type and HR mutants, which was not found in MGMT transfected cells. The gammaH2AX foci formed in response to O(6)MeG declined later in wild-type but not in HR-defective cells. The data support a model where DSBs are formed in response to O(6)MeG in the post-treatment cell cycle, which are repaired by HR, but not NHEJ, in a process that leads to SCEs. Therefore, HR can be considered as a mechanism that causes tolerance of O(6)MeG adducts. The data implicate that down-regulation or inhibition of HR might be a powerful strategy in improving cancer therapy with methylating agents.
Authors:
Wynand P Roos; Teodora Nikolova; Steve Quiros; Steffen C Naumann; Olivia Kiedron; Małgorzata Z Zdzienicka; Bernd Kaina
Related Documents :
8832129 - Bloom's syndrome. xix. cytogenetic and population evidence for genetic heterogeneity.
18215639 - Effect of static pressure on intracellular ph of adhesive chinese hamster ovary cells.
6621579 - Short-term tests for transplacentally active carcinogens. induction of sister-chromatid...
17358029 - Relative mutagenic potencies of several nucleoside analogs, alone or in drug pairs, at ...
9642289 - Genetic evidence that phosphatidylserine synthase ii catalyzes the conversion of phosph...
8942999 - Recurrent g-to-a substitution in a single codon of srebp cleavage-activating protein ca...
16656999 - The induction of biplanar growth in fern gametophytes in the presence of rna base analo...
15671069 - Physical and functional association of migfilin with cell-cell adhesions.
20534549 - Activity of any class ia pi3k isoform can sustain cell proliferation and survival.
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-10-21
Journal Detail:
Title:  DNA repair     Volume:  8     ISSN:  1568-7864     ISO Abbreviation:  DNA Repair (Amst.)     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2008-12-01     Completed Date:  2009-02-26     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101139138     Medline TA:  DNA Repair (Amst)     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  72-86     Citation Subset:  IM    
Affiliation:
Department of Toxicology, University of Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis*
BRCA2 Protein / genetics*
CHO Cells
Cell Death
Chromosome Aberrations
Cricetinae
Cricetulus
DNA Breaks, Double-Stranded*
DNA Repair*
DNA-Binding Proteins / genetics*
Dacarbazine / analogs & derivatives,  pharmacology
Down-Regulation
Fluorescent Antibody Technique
Guanine / analogs & derivatives*,  metabolism
Mice
Mutation
O(6)-Methylguanine-DNA Methyltransferase / genetics,  metabolism
Recombination, Genetic
Sister Chromatid Exchange / genetics*
Transfection
Chemical
Reg. No./Substance:
0/BRCA2 Protein; 0/DNA-Binding Proteins; 20535-83-5/O-(6)-methylguanine; 4342-03-4/Dacarbazine; 73-40-5/Guanine; 85622-93-1/temozolomide; EC 2.1.1.63/O(6)-Methylguanine-DNA Methyltransferase

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


Previous Document:  Coumarinic derivatives show anti-inflammatory effects on alveolar macrophages, but their anti-elasta...
Next Document:  Sympathetic drive is modulated by central chemoreceptor activation.