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DNA replication error-induced extinction of diploid yeast

Herr, Alan J ; Kennedy, Scott R ; Knowels, Gary M ; Schultz, Eric M ; Preston, Bradley D

Genetics, March 2014, Vol.196(3), pp.677-91 [Tạp chí có phản biện]

E-ISSN: 1943-2631 ; PMID: 24388879 Version:1 ; DOI: 10.1534/genetics.113.160960

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  • Nhan đề:
    DNA replication error-induced extinction of diploid yeast
  • Tác giả: Herr, Alan J ; Kennedy, Scott R ; Knowels, Gary M ; Schultz, Eric M ; Preston, Bradley D
  • Chủ đề: DNA Replication and Repair ; Cancer ; Lethal Mutagenesis ; Mutational Robustness ; Polymerase Fidelity ; DNA Replication ; DNA Polymerase III -- Genetics ; Saccharomyces Cerevisiae -- Enzymology ; Saccharomyces Cerevisiae Proteins -- Genetics
  • Là 1 phần của: Genetics, March 2014, Vol.196(3), pp.677-91
  • Mô tả: Genetic defects in DNA polymerase accuracy, proofreading, or mismatch repair (MMR) induce mutator phenotypes that accelerate adaptation of microbes and tumor cells. Certain combinations of mutator alleles synergistically increase mutation rates to levels that drive extinction of haploid cells. The maximum tolerated mutation rate of diploid cells is unknown. Here, we define the threshold for replication error-induced extinction (EEX) of diploid Saccharomyces cerevisiae. Double-mutant pol3 alleles that carry mutations for defective DNA polymerase-δ proofreading (pol3-01) and accuracy (pol3-L612M or pol3-L612G) induce strong mutator phenotypes in heterozygous diploids (POL3/pol3-01,L612M or POL3/pol3-01,L612G). Both pol3-01,L612M and pol3-01,L612G alleles are lethal in the homozygous state; cells with pol3-01,L612M divide up to 10 times before arresting at random stages in the cell cycle. Antimutator eex mutations in the pol3 alleles suppress this lethality (pol3-01,L612M,eex or pol3-01,L612G,eex). MMR defects synergize with pol3-01,L612M,eex and pol3-01,L612G,eex alleles, increasing mutation rates and impairing growth. Conversely, inactivation of the Dun1 S-phase checkpoint kinase suppresses strong pol3-01,L612M,eex and pol3-01,L612G,eex mutator phenotypes as well as the lethal pol3-01,L612M phenotype. Our results reveal that the lethal error threshold in diploids is 10 times higher than in haploids and likely determined by homozygous inactivation of essential genes. Pronounced loss of fitness occurs at mutation rates well below the lethal threshold, suggesting that mutator-driven cancers may be susceptible to drugs that exacerbate replication errors.
  • Ngôn ngữ: English
  • Số nhận dạng: E-ISSN: 1943-2631 ; PMID: 24388879 Version:1 ; DOI: 10.1534/genetics.113.160960

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