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    
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.
Wynand P Roos; Teodora Nikolova; Steve Quiros; Steffen C Naumann; Olivia Kiedron; Małgorzata Z Zdzienicka; Bernd Kaina
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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    
Department of Toxicology, University of Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
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MeSH Terms
BRCA2 Protein / genetics*
CHO Cells
Cell Death
Chromosome Aberrations
DNA Breaks, Double-Stranded*
DNA Repair*
DNA-Binding Proteins / genetics*
Dacarbazine / analogs & derivatives,  pharmacology
Fluorescent Antibody Technique
Guanine / analogs & derivatives*,  metabolism
O(6)-Methylguanine-DNA Methyltransferase / genetics,  metabolism
Recombination, Genetic
Sister Chromatid Exchange / genetics*
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 Methyltransferase

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

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