title: High doses of SN1 type methylating agents activate DNA damage signaling cascades that are largely independent of mismatch repair.
abstract: Methylating agents of the SN1 type represent an important class of cancer chemotherapeutics. Efficient killing by clinically-relevant doses of these agents requires cell division and low levels or absence of the repair enzyme methylguanine methyl transferase (MGMT). The process requires also an active mismatch repair (MMR) system, as treatment of cells with the prototypic methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) could be shown to trigger a delayed cell cycle arrest, which was absolutely MMR-dependent. We now show that DNA damage signaling activated by high doses of MNNG is very rapid and largely MMR-independent. However, the MMR system still contributes towards cell killing, as MMR deficiency favors the long-term survival of the cells, albeit to a substantially smaller extent than when low MNNG concentrations are deployed.
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland.
authors.forename: Lovorka
authors.initials: L
authors.lastname: Stojic
authors.forename: Petr
authors.initials: P
authors.lastname: Cejka
authors.forename: Josef
authors.initials: J
authors.lastname: Jiricny
mesh_terms: D020137:Base Pair Mismatch; D002460:Cell Line; D002470:Cell Survival; D004249:DNA Damage; D019175:DNA Methylation; D004260:DNA Repair; D004261:DNA Replication; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008769:Methylnitronitrosoguanidine / Q000737:chemistry; D008856:Microscopy, Fluorescence; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000737:chemistry; D010766:Phosphorylation; D016196:S Phase; D015398:Signal Transduction; D013778:Tetrazolium Salts / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry; D013997:Time Factors
chemical_list: D013778:Tetrazolium Salts; D013844:Thiazoles; D008769:Methylnitronitrosoguanidine; D019853:O(6)-Methylguanine-DNA Methyltransferase; C022616:thiazolyl blue