title: The translesion polymerase Rev3L in the tolerance of alkylating anticancer drugs.
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 zeta, 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.
authors.affiliation: Institute of Toxicology, University Medicine Mainz, Mainz D-55131, Germany.
authors.forename: Wynand Paul
authors.initials: WP
authors.lastname: Roos
authors.forename: Anastasia
authors.initials: A
authors.lastname: Tsaalbi-Shtylik
authors.forename: Roman
authors.initials: R
authors.lastname: Tsaryk
authors.forename: Fatma
authors.initials: F
authors.lastname: Güvercin
authors.forename: Niels
authors.initials: N
authors.lastname: de Wind
authors.forename: Bernd
authors.initials: B
authors.lastname: Kaina
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D003606:Dacarbazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009607:Nitrosourea Compounds / Q000009:adverse effects / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000009:adverse effects / Q000494:pharmacology*; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D003606:Dacarbazine; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; D000077204:Temozolomide; C054368:fotemustine; C486862:REV3L protein, mouse