Retrotransposon overdose and genome integrity

Yeast and mammalian genomes are replete with nearly identical copies of long dispersed repeats in the form of retrotransposons. Mechanisms clearly exist to maintain genome structure in the face of potential rearrangement between the dispersed repeats, but the nature of this machinery is poorly under...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 106; no. 33; pp. 13927 - 13932
Main Authors Scheifele, Lisa Z, Cost, Gregory J, Zupancic, Margaret L, Caputo, Emerita M, Boeke, Jef D
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 18.08.2009
National Acad Sciences
Subjects
Biological Sciences
Chromosome aberrations
Chromosomes
Chromosomes, Fungal
Deoxyribonucleic acid
DNA
DNA biosynthesis
DNA Damage
DNA Repair
DNA Replication
DNA, Fungal - genetics
Fungal Proteins - genetics
Gene Rearrangement
Genes
Genome
Genome, Fungal
Genomes
Genomics
Growth rate
Models, Genetic
Mutation
Overdose
Plasmids
Plasmids - metabolism
Recombination
Recombination, Genetic
Repeated DNA sequences
Replication
Retroelements
Retrotransposons
Saccharomyces cerevisiae
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae Proteins - genetics
Yeast
Yeasts
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Summary:Yeast and mammalian genomes are replete with nearly identical copies of long dispersed repeats in the form of retrotransposons. Mechanisms clearly exist to maintain genome structure in the face of potential rearrangement between the dispersed repeats, but the nature of this machinery is poorly understood. Here we describe a series of distinct "retrotransposon overdose" (RO) lineages in which the number of Ty1 elements in the Saccharomyces cerevisiae genome has been increased by as much as 10 fold. Although these RO strains are remarkably normal in growth rate, they demonstrate an intrinsic supersensitivity to DNA-damaging agents. We describe the identification of mutants in the DNA replication pathway that enhance this RO-specific DNA damage supersensitivity by promoting ectopic recombination between Ty1 elements. Abrogation of normal DNA replication leads to rampant genome instability primarily in the form of chromosomal aberrations and confirms the central role of DNA replication accuracy in the stabilization of repetitive DNA.
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1Present address: Department of Biology, Loyola College, Baltimore, MD 21210.
Communicated by Thomas D. Petes, Duke University Medical Center, Durham, NC, June 19, 2009
2Present address: Sangamo BioSciences, Richmond, CA 94804.
Author contributions: L.Z.S., G.J.C., and J.D.B. designed research; L.Z.S., G.J.C., M.L.Z., and E.M.C. performed research; L.Z.S., G.J.C., M.L.Z., and E.M.C. analyzed data; and L.Z.S. and J.D.B. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0906552106