In addition to spellchecking during DNA replication and modulating recombination, DNA mismatch repair (MMR) promotes cytotoxic responses to certain DNA-damaging agents [1]. In mammalian cells, the best-studied response is to S(n)1-type methylating agents, including N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) [1]. Notably, MMR-deficient mammalian cells are resistant to the cytotoxic effects of these agents. A recent report showed that MMR deficiency conferred resistance to MNNG in yeast cells crippled for both homologous recombination (rad52Delta) and the detoxifying enzyme methylguanine methyltransferase (mgt1Delta)[2]. To better understand the response, we searched for additional genes modulating sensitivity to MNNG in rad52Deltamgt1Delta budding yeast. In addition to alleles of known MMR genes, we isolated an allele of DCD1 encoding the enzyme deoxycytidylate deaminase, which influences the dCTP:dTTP nucleotide pool ratio by catalyzing the conversion of dCMP to dUMP [3]. Models of the MMR-dependent cytotoxic response to S(n)1-type methylating agents have included the incorporation of dTTP opposite O(6)-methyl guanine (O(6met)G) in the template [1]. Our findings lend further support to this aspect of the MMR-dependent response and highlight a mechanism for 'methylation' resistance that may be of therapeutic relevance for human cancer.

• PMID: 17803923
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Journal Article | Research Support, N.I.H., Extramural | Research Support, U.S. Gov't, Non-P.H.S.

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Liskay RM, Wheeler LJ, Mathews CK, Erdeniz N

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