Involvement of deoxycytidylate deaminase in the response to Sn1-type methylation DNA damage in budding yeast

R. Michael Liskay; Linda J. Wheeler; Christopher K. Mathews; Naz Erdeniz

doi:10.1016/j.cub.2007.07.028

Involvement of deoxycytidylate deaminase in the response to S_n1-type methylation DNA damage in budding yeast

R. Michael Liskay, Linda J. Wheeler, Christopher K. Mathews, Naz Erdeniz

Research output: Contribution to journal › Letter › peer-review

2 Scopus citations

Abstract

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_n1-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 (rad52Δ) and the detoxifying enzyme methylguanine methyltransferase (mgt1Δ) [2]. To better understand the response, we searched for additional genes modulating sensitivity to MNNG in rad52Δ mgt1Δ 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_n1-type methylating agents have included the incorporation of dTTP opposite O⁶-methyl guanine (O^6metG) 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.

Original language	English (US)
Pages (from-to)	R755-R757
Journal	Current Biology
Volume	17
Issue number	17
DOIs	https://doi.org/10.1016/j.cub.2007.07.028
State	Published - Sep 4 2007
Externally published	Yes

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)

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10.1016/j.cub.2007.07.028

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@article{04c872103f864ddfa1173041a2a0a4f4,

title = "Involvement of deoxycytidylate deaminase in the response to Sn1-type methylation DNA damage in budding yeast",

abstract = "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 Sn1-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 (rad52Δ) and the detoxifying enzyme methylguanine methyltransferase (mgt1Δ) [2]. To better understand the response, we searched for additional genes modulating sensitivity to MNNG in rad52Δ mgt1Δ 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 Sn1-type methylating agents have included the incorporation of dTTP opposite O6-methyl guanine (O6metG) 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.",

author = "Liskay, {R. Michael} and Wheeler, {Linda J.} and Mathews, {Christopher K.} and Naz Erdeniz",

note = "Funding Information: We thank Andrew Buermeyer, Jennifer Johnson, Ashleigh Miller and Sandra Dudley for critical reading of the manuscript. This work was supported by U.S. Army Research Office Grant No. W911NF-06-1-0110 to C.K.M. and by National Institutes of Health grant 5R01 GM45413 to R.M.L. ",

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AU - Liskay, R. Michael

AU - Wheeler, Linda J.

AU - Mathews, Christopher K.

AU - Erdeniz, Naz

N1 - Funding Information: We thank Andrew Buermeyer, Jennifer Johnson, Ashleigh Miller and Sandra Dudley for critical reading of the manuscript. This work was supported by U.S. Army Research Office Grant No. W911NF-06-1-0110 to C.K.M. and by National Institutes of Health grant 5R01 GM45413 to R.M.L.

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N2 - 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 Sn1-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 (rad52Δ) and the detoxifying enzyme methylguanine methyltransferase (mgt1Δ) [2]. To better understand the response, we searched for additional genes modulating sensitivity to MNNG in rad52Δ mgt1Δ 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 Sn1-type methylating agents have included the incorporation of dTTP opposite O6-methyl guanine (O6metG) 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.

AB - 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 Sn1-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 (rad52Δ) and the detoxifying enzyme methylguanine methyltransferase (mgt1Δ) [2]. To better understand the response, we searched for additional genes modulating sensitivity to MNNG in rad52Δ mgt1Δ 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 Sn1-type methylating agents have included the incorporation of dTTP opposite O6-methyl guanine (O6metG) 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.

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Involvement of deoxycytidylate deaminase in the response to S_n1-type methylation DNA damage in budding yeast

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