dNTP pool levels modulate mutator phenotypes of error-prone DNA polymerase ε variants
Significance An increased rate of mutation, or “mutator phenotype,” generates genetic diversity that can accelerate cancer progression or confer resistance to chemotherapy drugs. New therapeutic strategies are needed that target mutator phenotypes directly. Mutator phenotypes due to defects in DNA p...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 19; pp. E2457 - E2466 |
|---|---|
| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
12.05.2015
National Acad Sciences |
| Series | PNAS Plus |
| Subjects | |
| Online Access | Get full text |
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| Abstract | Significance An increased rate of mutation, or “mutator phenotype,” generates genetic diversity that can accelerate cancer progression or confer resistance to chemotherapy drugs. New therapeutic strategies are needed that target mutator phenotypes directly. Mutator phenotypes due to defects in DNA polymerase ε have been implicated in colorectal and endometrial cancers and may emerge in other cancers during treatment. Here, we show in budding yeast that such mutator phenotypes are influenced by the levels of dNTPs, the building blocks of DNA. Lowering dNTP pool levels lessens the mutator phenotypes, whereas increasing dNTP pools accentuates the mutator phenotypes. These findings suggest that mutator phenotypes due to error-prone polymerases may be modulated by treatments that target dNTP pools.
Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) ε mediates leading strand DNA replication. Proofreading defects in this enzyme drive a number of human malignancies. Here, using budding yeast, we show that mutator variants of Pol ε depend on damage uninducible (Dun)1, an S-phase checkpoint kinase that maintains dNTP levels during a normal cell cycle and up-regulates dNTP synthesis upon checkpoint activation. Deletion of DUN1 ( dun1 Δ) suppresses the mutator phenotype of pol2-4 (encoding Pol ε proofreading deficiency) and is synthetically lethal with pol2-M644G (encoding altered Pol ε base selectivity). Although pol2-4 cells cycle normally, pol2-M644G cells progress slowly through S-phase. The pol2-M644G cells tolerate deletions of mediator of the replication checkpoint ( MRC ) 1 ( mrc1 Δ) and radiation sensitive ( Rad ) 9 ( rad9 Δ), which encode mediators of checkpoint responses to replication stress and DNA damage, respectively. The pol2-M644G mutator phenotype is partially suppressed by mrc1 Δ but not rad9 Δ; neither deletion suppresses the pol2-4 mutator phenotype. Thus, checkpoint activation augments the Dun1 effect on replication fidelity but is not required for it. Deletions of genes encoding key Dun1 targets that negatively regulate dNTP synthesis, suppress the dun1 Δ pol2-M644G synthetic lethality and restore the mutator phenotype of pol2-4 in dun1 Δ cells. DUN1 pol2-M644G cells have constitutively high dNTP levels, consistent with checkpoint activation. In contrast, pol2-4 and POL2 cells have similar dNTP levels, which decline in the absence of Dun1 and rise in the absence of the negative regulators of dNTP synthesis. Thus, dNTP pool levels correlate with Pol ε mutator severity, suggesting that treatments targeting dNTP pools could modulate mutator phenotypes for therapy. |
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| AbstractList | Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) ε mediates leading strand DNA replication. Proofreading defects in this enzyme drive a number of human malignancies. Here, using budding yeast, we show that mutator variants of Pol ε depend on damage uninducible (Dun)1, an S-phase checkpoint kinase that maintains dNTP levels during a normal cell cycle and up-regulates dNTP synthesis upon checkpoint activation. Deletion of DUN1 (dun1Δ) suppresses the mutator phenotype of pol2-4 (encoding Pol ε proofreading deficiency) and is synthetically lethal with pol2-M644G (encoding altered Pol ε base selectivity). Although pol2-4 cells cycle normally, pol2-M644G cells progress slowly through S-phase. The pol2-M644G cells tolerate deletions of mediator of the replication checkpoint (MRC) 1 (mrc1Δ) and radiation sensitive (Rad) 9 (rad9Δ), which encode mediators of checkpoint responses to replication stress and DNA damage, respectively. The pol2-M644G mutator phenotype is partially suppressed by mrc1Δ but not rad9Δ; neither deletion suppresses the pol2-4 mutator phenotype. Thus, checkpoint activation augments the Dun1 effect on replication fidelity but is not required for it. Deletions of genes encoding key Dun1 targets that negatively regulate dNTP synthesis, suppress the dun1Δ pol2-M644G synthetic lethality and restore the mutator phenotype of pol2-4 in dun1Δ cells. DUN1 pol2-M644G cells have constitutively high dNTP levels, consistent with checkpoint activation. In contrast, pol2-4 and POL2 cells have similar dNTP levels, which decline in the absence of Dun1 and rise in the absence of the negative regulators of dNTP synthesis. Thus, dNTP pool levels correlate with Pol ε mutator severity, suggesting that treatments targeting dNTP pools could modulate mutator phenotypes for therapy. Significance An increased rate of mutation, or “mutator phenotype,” generates genetic diversity that can accelerate cancer progression or confer resistance to chemotherapy drugs. New therapeutic strategies are needed that target mutator phenotypes directly. Mutator phenotypes due to defects in DNA polymerase ε have been implicated in colorectal and endometrial cancers and may emerge in other cancers during treatment. Here, we show in budding yeast that such mutator phenotypes are influenced by the levels of dNTPs, the building blocks of DNA. Lowering dNTP pool levels lessens the mutator phenotypes, whereas increasing dNTP pools accentuates the mutator phenotypes. These findings suggest that mutator phenotypes due to error-prone polymerases may be modulated by treatments that target dNTP pools. Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) ε mediates leading strand DNA replication. Proofreading defects in this enzyme drive a number of human malignancies. Here, using budding yeast, we show that mutator variants of Pol ε depend on damage uninducible (Dun)1, an S-phase checkpoint kinase that maintains dNTP levels during a normal cell cycle and up-regulates dNTP synthesis upon checkpoint activation. Deletion of DUN1 ( dun1 Δ) suppresses the mutator phenotype of pol2-4 (encoding Pol ε proofreading deficiency) and is synthetically lethal with pol2-M644G (encoding altered Pol ε base selectivity). Although pol2-4 cells cycle normally, pol2-M644G cells progress slowly through S-phase. The pol2-M644G cells tolerate deletions of mediator of the replication checkpoint ( MRC ) 1 ( mrc1 Δ) and radiation sensitive ( Rad ) 9 ( rad9 Δ), which encode mediators of checkpoint responses to replication stress and DNA damage, respectively. The pol2-M644G mutator phenotype is partially suppressed by mrc1 Δ but not rad9 Δ; neither deletion suppresses the pol2-4 mutator phenotype. Thus, checkpoint activation augments the Dun1 effect on replication fidelity but is not required for it. Deletions of genes encoding key Dun1 targets that negatively regulate dNTP synthesis, suppress the dun1 Δ pol2-M644G synthetic lethality and restore the mutator phenotype of pol2-4 in dun1 Δ cells. DUN1 pol2-M644G cells have constitutively high dNTP levels, consistent with checkpoint activation. In contrast, pol2-4 and POL2 cells have similar dNTP levels, which decline in the absence of Dun1 and rise in the absence of the negative regulators of dNTP synthesis. Thus, dNTP pool levels correlate with Pol ε mutator severity, suggesting that treatments targeting dNTP pools could modulate mutator phenotypes for therapy. Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) ... mediates leading strand DNA replication. Proofreading defects in this enzyme drive a number of human malignancies. Here, using budding yeast, we show that mutator variants of Pol ... depend on damage uninducible (Dun)1, an S-phase checkpoint kinase that maintains dNTP levels during a normal cell cycle and up-regulates dNTP synthesis upon checkpoint activation. Deletion of DUN1 (dun1...) suppresses the mutator phenotype of pol2-4 (encoding Pol ... proofreading deficiency) and is synthetically lethal with pol2-M644G (encoding altered Pol ... base selectivity). Although pol2-4 cells cycle normally, pol2-M644G cells progress slowly through S-phase. The pol2-M644G cells tolerate deletions of mediator of the replication checkpoint (MRC) 1 (mrc1...) and radiation sensitive (Rad) 9 (rad9...), which encode mediators of checkpoint responses to replication stress and DNA damage, respectively. The pol2-M644G mutator phenotype is partially suppressed by mrc1... but not rad9...; neither deletion suppresses the pol2-4 mutator phenotype. Thus, checkpoint activation augments the Dun1 effect on replication fidelity but is not required for it. Deletions of genes encoding key Dun1 targets that negatively regulate dNTP synthesis, suppress the dun1... pol2-M644G synthetic lethality and restore the mutator phenotype of pol2-4 in dun1... cells. DUN1 pol2-M644G cells have constitutively high dNTP levels, consistent with checkpoint activation. In contrast, pol2-4 and POL2 cells have similar dNTP levels, which decline in the absence of Dun1 and rise in the absence of the negative regulators of dNTP synthesis. Thus, dNTP pool levels correlate with Pol ... mutator severity, suggesting that treatments targeting dNTP pools could modulate mutator phenotypes for therapy. (ProQuest: ... denotes formulae/symbols omitted.) Significance An increased rate of mutation, or “mutator phenotype,” generates genetic diversity that can accelerate cancer progression or confer resistance to chemotherapy drugs. New therapeutic strategies are needed that target mutator phenotypes directly. Mutator phenotypes due to defects in DNA polymerase ε have been implicated in colorectal and endometrial cancers and may emerge in other cancers during treatment. Here, we show in budding yeast that such mutator phenotypes are influenced by the levels of dNTPs, the building blocks of DNA. Lowering dNTP pool levels lessens the mutator phenotypes, whereas increasing dNTP pools accentuates the mutator phenotypes. These findings suggest that mutator phenotypes due to error-prone polymerases may be modulated by treatments that target dNTP pools. Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) ε mediates leading strand DNA replication. Proofreading defects in this enzyme drive a number of human malignancies. Here, using budding yeast, we show that mutator variants of Pol ε depend on damage uninducible (Dun)1, an S-phase checkpoint kinase that maintains dNTP levels during a normal cell cycle and up-regulates dNTP synthesis upon checkpoint activation. Deletion of DUN1 ( dun1 Δ) suppresses the mutator phenotype of pol2-4 (encoding Pol ε proofreading deficiency) and is synthetically lethal with pol2-M644G (encoding altered Pol ε base selectivity). Although pol2-4 cells cycle normally, pol2-M644G cells progress slowly through S-phase. The pol2-M644G cells tolerate deletions of mediator of the replication checkpoint ( MRC ) 1 ( mrc1 Δ) and radiation sensitive ( Rad ) 9 ( rad9 Δ), which encode mediators of checkpoint responses to replication stress and DNA damage, respectively. The pol2-M644G mutator phenotype is partially suppressed by mrc1 Δ but not rad9 Δ; neither deletion suppresses the pol2-4 mutator phenotype. Thus, checkpoint activation augments the Dun1 effect on replication fidelity but is not required for it. Deletions of genes encoding key Dun1 targets that negatively regulate dNTP synthesis, suppress the dun1 Δ pol2-M644G synthetic lethality and restore the mutator phenotype of pol2-4 in dun1 Δ cells. DUN1 pol2-M644G cells have constitutively high dNTP levels, consistent with checkpoint activation. In contrast, pol2-4 and POL2 cells have similar dNTP levels, which decline in the absence of Dun1 and rise in the absence of the negative regulators of dNTP synthesis. Thus, dNTP pool levels correlate with Pol ε mutator severity, suggesting that treatments targeting dNTP pools could modulate mutator phenotypes for therapy. Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) ε mediates leading strand DNA replication. Proofreading defects in this enzyme drive a number of human malignancies. Here, using budding yeast, we show that mutator variants of Pol ε depend on damage uninducible (Dun)1, an S-phase checkpoint kinase that maintains dNTP levels during a normal cell cycle and up-regulates dNTP synthesis upon checkpoint activation. Deletion ofDUN1(dun1Δ) suppresses the mutator phenotype ofpol2-4(encoding Pol ε proofreading deficiency) and is synthetically lethal withpol2-M644G(encoding altered Pol ε base selectivity). Althoughpol2-4cells cycle normally,pol2-M644Gcells progress slowly through S-phase. Thepol2-M644Gcells tolerate deletions of mediator of the replication checkpoint (MRC) 1 (mrc1Δ) and radiation sensitive (Rad) 9 (rad9Δ), which encode mediators of checkpoint responses to replication stress and DNA damage, respectively. Thepol2-M644Gmutator phenotype is partially suppressed bymrc1Δ but notrad9Δ; neither deletion suppresses thepol2-4mutator phenotype. Thus, checkpoint activation augments the Dun1 effect on replication fidelity but is not required for it. Deletions of genes encoding key Dun1 targets that negatively regulate dNTP synthesis, suppress thedun1Δpol2-M644Gsynthetic lethality and restore the mutator phenotype ofpol2-4indun1Δ cells.DUN1 pol2-M644Gcells have constitutively high dNTP levels, consistent with checkpoint activation. In contrast,pol2-4andPOL2cells have similar dNTP levels, which decline in the absence of Dun1 and rise in the absence of the negative regulators of dNTP synthesis. Thus, dNTP pool levels correlate with Pol ε mutator severity, suggesting that treatments targeting dNTP pools could modulate mutator phenotypes for therapy. An increased rate of mutation, or “mutator phenotype,” generates genetic diversity that can accelerate cancer progression or confer resistance to chemotherapy drugs. New therapeutic strategies are needed that target mutator phenotypes directly. Mutator phenotypes due to defects in DNA polymerase ε have been implicated in colorectal and endometrial cancers and may emerge in other cancers during treatment. Here, we show in budding yeast that such mutator phenotypes are influenced by the levels of dNTPs, the building blocks of DNA. Lowering dNTP pool levels lessens the mutator phenotypes, whereas increasing dNTP pools accentuates the mutator phenotypes. These findings suggest that mutator phenotypes due to error-prone polymerases may be modulated by treatments that target dNTP pools. Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) ε mediates leading strand DNA replication. Proofreading defects in this enzyme drive a number of human malignancies. Here, using budding yeast, we show that mutator variants of Pol ε depend on damage uninducible (Dun)1, an S-phase checkpoint kinase that maintains dNTP levels during a normal cell cycle and up-regulates dNTP synthesis upon checkpoint activation. Deletion of DUN1 ( dun1 Δ) suppresses the mutator phenotype of pol2-4 (encoding Pol ε proofreading deficiency) and is synthetically lethal with pol2-M644G (encoding altered Pol ε base selectivity). Although pol2-4 cells cycle normally, pol2-M644G cells progress slowly through S-phase. The pol2-M644G cells tolerate deletions of mediator of the replication checkpoint ( MRC ) 1 ( mrc1 Δ) and radiation sensitive ( Rad ) 9 ( rad9 Δ), which encode mediators of checkpoint responses to replication stress and DNA damage, respectively. The pol2-M644G mutator phenotype is partially suppressed by mrc1 Δ but not rad9 Δ; neither deletion suppresses the pol2-4 mutator phenotype. Thus, checkpoint activation augments the Dun1 effect on replication fidelity but is not required for it. Deletions of genes encoding key Dun1 targets that negatively regulate dNTP synthesis, suppress the dun1 Δ pol2-M644G synthetic lethality and restore the mutator phenotype of pol2-4 in dun1 Δ cells. DUN1 pol2-M644G cells have constitutively high dNTP levels, consistent with checkpoint activation. In contrast, pol2-4 and POL2 cells have similar dNTP levels, which decline in the absence of Dun1 and rise in the absence of the negative regulators of dNTP synthesis. Thus, dNTP pool levels correlate with Pol ε mutator severity, suggesting that treatments targeting dNTP pools could modulate mutator phenotypes for therapy. |
| Author | Marjavaara, Lisette Herr, Alan J. Schultz, Eric M. Knowels, Gary M. Fox, Edward J. Chabes, Andrei Williams, Lindsey N. |
| Author_xml | – sequence: 1 givenname: Lindsey N. surname: Williams fullname: Williams, Lindsey N. organization: Department of Pathology, University of Washington, Seattle, WA 98195 – sequence: 2 givenname: Lisette surname: Marjavaara fullname: Marjavaara, Lisette organization: Department of Medical Biochemistry and Biophysics, Umeå University, SE 90197, Umeå, Sweden, Laboratory for Molecular Infection Medicine Sweden, Umeå University, SE 90197, Umeå, Sweden – sequence: 3 givenname: Gary M. surname: Knowels fullname: Knowels, Gary M. organization: Department of Pathology, University of Washington, Seattle, WA 98195 – sequence: 4 givenname: Eric M. surname: Schultz fullname: Schultz, Eric M. organization: Department of Pathology, University of Washington, Seattle, WA 98195 – sequence: 5 givenname: Edward J. surname: Fox fullname: Fox, Edward J. organization: Department of Pathology, University of Washington, Seattle, WA 98195 – sequence: 6 givenname: Andrei surname: Chabes fullname: Chabes, Andrei organization: Department of Medical Biochemistry and Biophysics, Umeå University, SE 90197, Umeå, Sweden, Laboratory for Molecular Infection Medicine Sweden, Umeå University, SE 90197, Umeå, Sweden – sequence: 7 givenname: Alan J. surname: Herr fullname: Herr, Alan J. organization: Department of Pathology, University of Washington, Seattle, WA 98195 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25827226$$D View this record in MEDLINE/PubMed https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-101547$$DView record from Swedish Publication Index |
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| Keywords | cancer polymerase fidelity lethal mutagenesis DNA replication and repair |
| Language | English |
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| Notes | http://dx.doi.org/10.1073/pnas.1422948112 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Lawrence A. Loeb, University of Washington School of Medicine, Seattle, WA, and accepted by the Editorial Board March 5, 2015 (received for review December 1, 2014) Author contributions: L.N.W., A.C., and A.J.H. designed research; L.N.W., L.M., G.M.K., E.M.S., E.J.F., A.C., and A.J.H. performed research; L.N.W., E.J.F., A.C., and A.J.H. contributed new reagents/analytic tools; L.N.W., L.M., G.M.K., E.M.S., E.J.F., A.C., and A.J.H. analyzed data; and L.N.W., L.M., G.M.K., E.M.S., A.C., and A.J.H. wrote the paper. |
| ORCID | 0000-0003-1708-8259 |
| OpenAccessLink | https://www.pnas.org/content/pnas/112/19/E2457.full.pdf |
| PMID | 25827226 |
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| PublicationDate | 2015-05-12 |
| PublicationDateYYYYMMDD | 2015-05-12 |
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| PublicationDecade | 2010 |
| PublicationPlace | United States |
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| PublicationTitle | Proceedings of the National Academy of Sciences - PNAS |
| PublicationTitleAlternate | Proc Natl Acad Sci U S A |
| PublicationYear | 2015 |
| Publisher | National Academy of Sciences National Acad Sciences |
| Publisher_xml | – name: National Academy of Sciences – name: National Acad Sciences |
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| Snippet | Significance An increased rate of mutation, or “mutator phenotype,” generates genetic diversity that can accelerate cancer progression or confer resistance to... Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) ε mediates leading strand DNA replication. Proofreading defects in... Significance An increased rate of mutation, or “mutator phenotype,” generates genetic diversity that can accelerate cancer progression or confer resistance to... Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) ... mediates leading strand DNA replication. Proofreading defects... An increased rate of mutation, or “mutator phenotype,” generates genetic diversity that can accelerate cancer progression or confer resistance to chemotherapy... |
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| SubjectTerms | Alleles Antineoplastic Agents - chemistry Antineoplastic Agents - therapeutic use Biological Sciences Cell Cycle DNA Mutational Analysis DNA Replication DNA-Directed DNA Polymerase - genetics Genetic Variation Humans Mutagenesis Mutation Neoplasms - drug therapy Neoplasms - genetics Nucleotides - chemistry Phenotype Phosphates - chemistry Plasmids - metabolism PNAS Plus S Phase Saccharomyces cerevisiae Saccharomyces cerevisiae - genetics Saccharomyces cerevisiae - metabolism |
| Title | dNTP pool levels modulate mutator phenotypes of error-prone DNA polymerase ε variants |
| URI | https://www.jstor.org/stable/26462780 http://www.pnas.org/content/112/19/E2457.abstract https://www.ncbi.nlm.nih.gov/pubmed/25827226 https://search.proquest.com/docview/1680960085 https://search.proquest.com/docview/1694981495 https://pubmed.ncbi.nlm.nih.gov/PMC4434706 https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-101547 |
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