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Homologous recombination rescues mismatch-repair-dependent cytotoxicity of S(N)1-type methylating agents in S. cerevisiae

Cejka, Petr and Mojas, Nina and Gillet, Ludovic and Schär, Primo and Jiricny, Josef. (2005) Homologous recombination rescues mismatch-repair-dependent cytotoxicity of S(N)1-type methylating agents in S. cerevisiae. Current biology, Vol. 15, H. 15. pp. 1395-1400.

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Official URL: http://edoc.unibas.ch/dok/A5253999

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Abstract

Resistance of mammalian cells to S(N)1-type methylating agents such as N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) generally arises through increased expression of methylguanine methyltransferase (MGMT), which reverts the cytotoxic O(6)-methylguanine ((Me)G) to guanine, or through inactivation of the mismatch repair (MMR) system, which triggers cell death through aberrant processing of (Me)G/T mispairs generated during DNA replication when MGMT capacity is exceeded. Given that MMR and (Me)G-detoxifying proteins are functionally conserved through evolution, and that MMR-deficient Escherichia coli dam(-) strains are also resistant to MNNG, the finding that MMR status did not affect the sensitivity of Saccharomyces cerevisiae to MNNG was unexpected. Because (Me)G residues in DNA trigger homologous recombination (HR), we wondered whether the efficient HR in S. cerevisiae might alleviate the cytotoxic effects of (Me)G processing. We now show that HR inactivation sensitizes S. cerevisiae to MNNG and that, as in human cells, defects in the MMR genes MLH1 and MSH2 rescue this sensitivity. Inactivation of the EXO1 gene, which encodes the only exonuclease implicated in MMR to date, failed to rescue the hypersensitivity, which implies that scExo1 is not involved in the processing of (Me)G residues by the S. cerevisiae MMR system.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Molecular Genetics (Schär)
UniBasel Contributors:Schär, Primo Leo
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Cell Press
ISSN:0960-9822
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:22 Mar 2012 14:23
Deposited On:22 Mar 2012 13:33

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