Mutagenesis Advance Access published online on November 17, 2009
Mutagenesis, doi:10.1093/mutage/gep038
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Phosphotriester adducts (PTEs): DNA's overlooked lesion
1Radiation and Oxidative Stress Group, Biocentre, Department of Cancer Studies and Molecular Medicine, University of Leicester, University Road, Leicester LE1 7RH, UK 2Cancer Biomarkers and Prevention Group, Biocentre, Department of Cancer Studies and Molecular Medicine, University of Leicester, University Road, Leicester LE1 7RH, UK
In addition to reacting with DNA base moieties, many chemical genotoxins also react with the oxygen atoms of the internucleotidic phosphodiester linkages to form phosphotriester adducts (PTEs). In view of their stability under physiological conditions, it has been suggested that PTEs may be useful biomarkers for measuring cumulative genotoxin exposure. The methodology for their determination is varied and still not completely developed but includes determination of hydrolysis products and 32P-postlabelling approaches. More recently, transalkylation and direct mass spectrometry techniques have been devised, which give extra chemical information on the structures of the PTEs. The proportion of DNA damage formed as PTEs is much greater with SN1 compared to SN2 alkylating agents, and it has been shown in DNA that the formation of PTEs is partially sequence dependent. PTEs have been considered to be refractory to repair in mammalian cells but repair mechanisms have been found in prokaryotic cells, e.g. PTEs in Escherichia coli are repaired by O6-methylguanine-DNA methyltransferase (O6-MGT or Ada protein). However, studies on in vivo persistence of PTEs in mammalian systems have not ruled out the possibility of a contribution from an active repair process for PTEs. The biological significance of PTEs is largely unstudied and unknown, although effects of PTEs on DNA polymerases, and some exo- and endonucleases have been observed. Also site-specific PTEs impair the repair processing of adjacent sites of DNA damage, which may be a biological mechanism of importance for these lesions. In this review, we will consider the analytical methods available for the determination of PTEs, their stability in vitro and in vivo, the mechanisms for their repair, their possible biological significance and their potential role as biomarkers in human molecular epidemiology studies.
* To whom correspondence should be addressed. Cancer Biomarkers and Prevention Group, Biocentre, University of Leicester, University Road, Leicester LE1 7RH, UK. Tel: +44 116 2231823; Fax: +44 116 2231840; Email: pbf1{at}le.ac.uk
3 Present address: Boots Manufacturing, D10 Thane Road, Nottingham NG90 2DB, UK
Received on May 26, 2009; revised on September 14, 2009; accepted on September 15, 2009.