Skip Navigation



Carcinogenesis Advance Access published online on August 22, 2006
Carcinogenesis, doi:10.1093/carcin/bgl150
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrowOA All Versions of this Article:
28/2/356    most recent
bgl150v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Gottschalg, E.
Right arrow Articles by Shuker, D. E. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gottschalg, E.
Right arrow Articles by Shuker, D. E. G.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2006 The Author(s)
Received March 15, 2006
Revised July 18, 2006
Accepted August 8, 2006

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Potassium diazoacetate-induced p53 mutations in vitro in relation to formation of O6-carboxymethyl- and O6-methyl-2'-deoxyguanosine DNA adducts - relevance for gastrointestinal cancer

Elke Gottschalg 1 {dagger}, Gina B. Scott 2 {dagger}, Philip A. Burns 2, and David E. G. Shuker 3 *

1 MRC Toxicology Unit, Hodgkin Building, University of Leicester, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK; Present address: School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
2 Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds LS9 7TF, UK
3 Department of Chemistry, The Open University, Walton Hall, Milton Keynes MK7 6AA UK

* To whom correspondence should be addressed.
David E. G. Shuker, E-mail: d.e.g.shuker{at}open.ac.uk


  Abstract

Nitrosated glycine derivatives react with DNA to form O6-carboxymethyl-2'-deoxyguanosine (O6-CMdG) and O6-methyl-2'-deoxyguanosine (O6-MedG) adducts concurrently. O6-CMdG is not repaired by O6-alkylguanine alkyltransferases and might be expected to lead to mutations via a similar mechanism to O6-MedG. Potassium diazoacetate (KDA) is a stable form of nitrosated glycine and its ability to induce mutations in the p53 gene in a functional yeast assay was studied. Treatment of a plasmid containing the human p53 cDNA sequence with KDA afforded readily detectable levels of O6-CMdG and O6-MedG. The treated plasmid was used to transform yeast cells and coloured colonies harbouring a p53 sequence with functional mutations were detected. Recovery of the mutated plasmids followed by DNA sequencing enabled the mutation spectrum of KDA to be characterised. The most common mutations induced by KDA were substitutions with more than 50% occurring at GC base pairs. In contrast to the methylating agent methylnitrosourea which gives predominantly (>80%) GC->AT transitions, KDA produced almost equal amounts of transitions (GC->AT) and transversions (GC->TA and AT->TA). This difference is probably due to a different mode of base mispairing for O6-CMdG compared to O6-MedG. The pattern of mutations induced by KDA was very similar to the patterns observed in mutated p53 in human gastrointestinal tract tumours. These results are consistent with the hypothesis that nitrosation of glycine (or glycine derivatives) may contribute to characteristic human p53 mutation profiles. This conclusion is borne out by recent observations that O6-CMdG is present in human DNA both from blood and exfoliated colorectal cells and is consistent with recent epidemiological studies that have concluded that endogenous nitrosation arising from red meat consumption is related to an increased risk of colorectal cancer.

{dagger}EG and GBS contributed equally to this paper
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Nucleic Acids ResHome page
J. Wang and Y. Wang
Chemical synthesis of oligodeoxyribonucleotides containing N3- and O4-carboxymethylthymidine and their formation in DNA
Nucleic Acids Res., February 1, 2009; 37(2): 336 - 345.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
H. L. Greetham, S. A. Bingham, and P. A. Burns
Adduction of Human p53 Gene by Fecal Water: An In vitro Biomarker of Mutagenesis in the Human Large Bowel
Cancer Epidemiol. Biomarkers Prev., December 1, 2007; 16(12): 2681 - 2685.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.