Linked Life Data

10838139

Source:http://linkedlifedata.com/resource/pubmed/id/10838139

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1-2
pubmed:dateCreated
2000-7-27
pubmed:abstractText
In this contribution we discuss the gene- and cell type-specific repair of miscoding DNA alkylation products as a risk parameter in both mutation induction and malignant transformation by N-nitroso carcinogens. Upon exposure to N-nitroso compounds such as N-methyl-N-nitrosourea (MeNU) or N-ethyl-N-nitrosourea (EtNU), about a dozen different alkylation products are formed in cellular DNA. Among these are O(6)-methylguanine (O(6)-MeGua) and O(6)-ethylguanine (O(6)-EtGua), respectively, which differ only by one CH(2) group in their alkyl residue and, when unrepaired, cause G:C-->A:T transition mutations by anomalous base pairing during DNA replication. We have analyzed the global and gene-specific repair of O(6)-MeGua and O(6)-EtGua in target cell DNA, ras gene mutation frequencies, and tumor incidence, in the model of mammary carcinogenesis induced in 50-day-old female Sprague-Dawley rats by a single application of MeNU or EtNU. Both carcinogens induce histologically indistinguishable mammary adenocarcinomas at high yield. In the target mammary epithelia, O(6)-MeGua is repaired at similar slow rates in both transcriptionally active genes (Ha-ras, beta-actin), silent genes (lgE heavy chain), and in bulk DNA, by the one-step repair protein O(6)-alkylguanine-DNA alkyltransferase (MGMT; low level of expression in the target cells). The slow repair of O(6)-MeGua translates into a high frequency of mutations at the central position of Ha-ras codon 12 (GGA) in MeNU-induced tumors. O(6)-EtGua, however, is removed approximately 20 times faster than O(6)-MeGua selectively from transcribed genes via an MGMT independent, as yet uncharacterized excision mechanism. Accordingly, no Ha-ras codon 12 mutations are found in the EtNU-induced mammary tumors. Neither MeNU- nor EtNU-induced tumors exhibit mutations at codons 13 and 61 of Ha-ras or at codons 12, 13 and 61 of Ki-ras. While a moderate surplus MGMT activity of the target cells - contributed by a bacterial MGMT transgene (ada) - significantly counteracts mammary tumorigenesis in MeNU-exposed rats, this is not the case in the EtNU-treated animals. Differential repair of structurally distinct DNA lesions in transcribed or (temporarily) silent genes thus determines the probability of mutation and, together with cell type-specific and interindividual differences in DNA repair capacity, influences carcinogenic risk.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0027-5107
pubmed:author
pubmed:issnType
Print
pubmed:day
30
pubmed:volume
450
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
139-53
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2000
pubmed:articleTitle
Role of DNA repair in carcinogen-induced ras mutation.
pubmed:affiliation
Institute of Cell Biology (Cancer Research), University of Essen Medical School and West German Cancer Center Essen, Hufelandstrasse 55, D-45122, Essen, Germany.
pubmed:publicationType
Journal Article, Review, Research Support, Non-U.S. Gov't