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The Translesion Polymerase Rev3L in the Tolerance of Alkylating Anticancer Drugs

Wynand Paul Roos, Anastasia Tsaalbi-Shtylik, Roman Tsaryk, Fatma Güvercin, Niels de Wind and Bernd Kaina
Molecular Pharmacology October 2009, 76 (4) 927-934; DOI: https://doi.org/10.1124/mol.109.058131
Wynand Paul Roos
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Anastasia Tsaalbi-Shtylik
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Roman Tsaryk
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Fatma Güvercin
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Niels de Wind
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Bernd Kaina
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Abstract

Temozolomide and fotemustine, representing methylating and chloroethylating agents, respectively, are used in the treatment of glioma and malignant melanoma. Because chemoresistance of these tumors is a common phenomenon, identification of the underlying mechanisms is needed. Here we show that Rev3L, the catalytic subunit of the translesion DNA polymerase ζ, mediates resistance to both temozolomide and fotemustine. Rev3L knockout cells are hypersensitive to both agents. It is remarkable that cells heterozygous for Rev3L showed an intermediate sensitivity. Rev3L is not involved in the tolerance of the toxic O6-methylguanine lesion. However, a possible role of Rev3L in the tolerance of O6-chloroethylguanine or the subsequently formed N1-guanine-N3-cytosine interstrand cross-link is shown. Rev3L had no influence on base excision repair (BER) of the N-alkylation lesions but is very likely to be involved in the tolerance of N-alkylations or apurinic/apyrimidinic sites originating from them. We also show that Rev3L exerts its protective effect in replicating cells and that loss of Rev3L leads to a significant increase in DNA double-strand breaks after temozolomide and fotemustine treatment. These data show that Rev3L contributes to temozolomide and fotemustine resistance, thus acting in concert with O6-methylguanine-DNA methyltransferase, BER, mismatch repair, and double-strand break repair in defense against simple alkylating anticancer drugs.

  • MGMT, O6-methylguanine-DNA methyltransferase
  • BER, base excision repair
  • DSB, DNA double-strand break
  • ssb, single-strand break
  • TLS, translesion DNA synthesis
  • O6BG, O6-benzylguanine
  • MNNG, N-methyl-N′-nitro-N-nitrosoguanidine
  • Pol, polymerase
  • DMSO, dimethyl sulfoxide
  • AP, apurinic/apyrimidinic
  • PBS, phosphate-buffered saline.

Footnotes

  • This work was supported by Deutsche Forschungsgemeinschaft [Grant DFG-Ka 724]; the German Cancer Foundation [Grant Ka-106748]; the Dutch Cancer Foundation [Grant UL 2001-2517]; and the European Union [Grant EU-IP FP6-512113].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • ABBREVIATIONS:

    • Received May 27, 2009.
    • Accepted July 27, 2009.
  • © 2009 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 76 (4)
Molecular Pharmacology
Vol. 76, Issue 4
October 2009
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The Translesion Polymerase Rev3L in the Tolerance of Alkylating Anticancer Drugs

Wynand Paul Roos, Anastasia Tsaalbi-Shtylik, Roman Tsaryk, Fatma Güvercin, Niels de Wind and Bernd Kaina
Molecular Pharmacology October 1, 2009, 76 (4) 927-934; DOI: https://doi.org/10.1124/mol.109.058131

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The Translesion Polymerase Rev3L in the Tolerance of Alkylating Anticancer Drugs

Wynand Paul Roos, Anastasia Tsaalbi-Shtylik, Roman Tsaryk, Fatma Güvercin, Niels de Wind and Bernd Kaina
Molecular Pharmacology October 1, 2009, 76 (4) 927-934; DOI: https://doi.org/10.1124/mol.109.058131
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