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


Cejka, P; Mojas, N; Gillet, L; Schär, P; Jiricny, J (2005). Homologous recombination rescues mismatch-repair-dependent cytotoxicity of S(N)1-type methylating agents in S. cerevisiae. Current Biology, 15(15):1395-1400.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2005
Deposited On:09 Jul 2010 13:19
Last Modified:05 Apr 2016 14:09
Publisher:Elsevier
ISSN:0960-9822
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.cub.2005.07.032
PubMed ID:16085492

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