Document Detail


Both base excision repair and O6-methylguanine-DNA methyltransferase protect against methylation-induced colon carcinogenesis.
MedLine Citation:
PMID:  20732909     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Methylating agents are widely distributed environmental carcinogens. Moreover, they are being used in cancer chemotherapy. The primary target of methylating agents is DNA, and therefore, DNA repair is the first-line barrier in defense against their toxic and carcinogenic effects. Methylating agents induce in the DNA O(6)-methylguanine (O(6)MeG) and methylations of the ring nitrogens of purines. The lesions are repaired by O(6)-methylguanine-DNA methyltransferase (Mgmt) and by enzymes of the base excision repair (BER) pathway, respectively. Whereas O(6)MeG is well established as a pre-carcinogenic lesion, little is known about the carcinogenic potency of base N-alkylation products such as N3-methyladenine and N3-methylguanine. To determine their role in cancer formation and the role of BER in cancer protection, we checked the response of mice with a targeted gene disruption of Mgmt or N-alkylpurine-DNA glycosylase (Aag) or both Mgmt and Aag, to azoxymethane (AOM)-induced colon carcinogenesis, using non-invasive mini-colonoscopy. We demonstrate that both Mgmt- and Aag-null mice show a higher colon cancer frequency than the wild-type. With a single low dose of AOM (3 mg/kg) Aag-null mice showed an even stronger tumor response than Mgmt-null mice. The data provide evidence that both BER initiated by Aag and O(6)MeG reversal by Mgmt are required for protection against alkylation-induced colon carcinogenesis. Further, the data indicate that non-repaired N-methylpurines are not only pre-toxic but also pre-carcinogenic DNA lesions.
Authors:
Stefan Wirtz; Georg Nagel; Leonid Eshkind; Markus F Neurath; Leona D Samson; Bernd Kaina
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-08-23
Journal Detail:
Title:  Carcinogenesis     Volume:  31     ISSN:  1460-2180     ISO Abbreviation:  Carcinogenesis     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-01     Completed Date:  2011-01-06     Revised Date:  2014-09-11    
Medline Journal Info:
Nlm Unique ID:  8008055     Medline TA:  Carcinogenesis     Country:  England    
Other Details:
Languages:  eng     Pagination:  2111-7     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Colonic Neoplasms / genetics,  prevention & control*
DNA Glycosylases / physiology
DNA Repair*
Female
Male
Methylation
Mice
Mice, Inbred C57BL
O(6)-Methylguanine-DNA Methyltransferase / physiology*
Grant Support
ID/Acronym/Agency:
R01 CA075576/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
EC 2.1.1.63/O(6)-Methylguanine-DNA Methyltransferase; EC 3.2.2.-/DNA Glycosylases; EC 3.2.2.21/DNA-3-methyladenine glycosidase II
Comments/Corrections

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


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