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    
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.
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
Colonic Neoplasms / genetics,  prevention & control*
DNA Glycosylases / physiology
DNA Repair*
Mice, Inbred C57BL
O(6)-Methylguanine-DNA Methyltransferase / physiology*
Grant Support
Reg. No./Substance:
EC Methyltransferase; EC 3.2.2.-/DNA Glycosylases; EC glycosidase II

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

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