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    The bacterial alkyltransferase-like (eATL) protein protects mammalian cells against methylating agent-induced toxicity.

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    Authors
    Tomaszowski, K
    Aasland, D
    Margison, Geoffrey P
    Williams, Emma L
    Pinder, Sarah
    Modesti, M
    Fuchs, R
    Kaina, B
    Affiliation
    Department of Toxicology, University Medical Center, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany
    Issue Date
    2015-01-31
    
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    Abstract
    In both pro- and eukaryotes, the mutagenic and toxic DNA adduct O(6)-methylguanine (O(6)MeG) is subject to repair by alkyltransferase proteins via methyl group transfer. In addition, in prokaryotes, there are proteins with sequence homology to alkyltransferases, collectively designated as alkyltransferase-like (ATL) proteins, which bind to O(6)-alkylguanine adducts and mediate resistance to alkylating agents. Whether such proteins might enable similar protection in higher eukaryotes is unknown. Here we expressed the ATL protein of Escherichia coli (eATL) in mammalian cells and addressed the question whether it is able to protect them against the cytotoxic effects of alkylating agents. The Chinese hamster cell line CHO-9, the nucleotide excision repair (NER) deficient derivative 43-3B and the DNA mismatch repair (MMR) impaired derivative Tk22-C1 were transfected with eATL cloned in an expression plasmid and the sensitivity to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was determined in reproductive survival, DNA double-strand break (DSB) and apoptosis assays. The results indicate that eATL expression is tolerated in mammalian cells and conferes protection against killing by MNNG in both wild-type and 43-3B cells, but not in the MMR-impaired cell line. The protection effect was dependent on the expression level of eATL and was completely ablated in cells co-expressing the human O(6)-methylguanine-DNA methyltransferase (MGMT). eATL did not protect against cytotoxicity induced by the chloroethylating agent lomustine, suggesting that O(6)-chloroethylguanine adducts are not target of eATL. To investigate the mechanism of protection, we determined O(6)MeG levels in DNA after MNNG treatment and found that eATL did not cause removal of the adduct. However, eATL expression resulted in a significantly lower level of DSBs in MNNG-treated cells, and this was concomitant with attenuation of G2 blockage and a lower level of apoptosis. The results suggest that eATL confers protection against methylating agents by masking O(6)MeG/thymine mispaired adducts, preventing them from becoming a substrate for mismatch repair-mediated DSB formation and cell death.
    Citation
    The bacterial alkyltransferase-like (eATL) protein protects mammalian cells against methylating agent-induced toxicity. 2015, 28C:14-20 DNA Repair
    Journal
    DNA Repair
    URI
    http://hdl.handle.net/10541/347215
    DOI
    10.1016/j.dnarep.2015.01.009
    PubMed ID
    25703834
    Type
    Article
    Language
    en
    ISSN
    1568-7856
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.dnarep.2015.01.009
    Scopus Count
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