RT Journal Article
SR Electronic
T1 The Translesion Polymerase Rev3L in the Tolerance of Alkylating Anticancer Drugs
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 927
OP 934
DO 10.1124/mol.109.058131
VO 76
IS 4
A1 Wynand Paul Roos
A1 Anastasia Tsaalbi-Shtylik
A1 Roman Tsaryk
A1 Fatma Güvercin
A1 Niels de Wind
A1 Bernd Kaina
YR 2009
UL http://molpharm.aspetjournals.org/content/76/4/927.abstract
AB 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. © 2009 The American Society for Pharmacology and Experimental Therapeutics