Retrotransposons and genome stability
Retrotransposons present a threat to genome stability as a result of their dispersed nature, with 32 copies of the Ty1 element per haploid yeast genome. Ty1 retrotransposons replicate through an RNA intermediate that is reverse-transcribed following encapsidation into a retrovirus-like particle, and then integrated into the host cell genome. These integrated Ty1 copies provide two challenges to genome stability: when Ty1 repeats are present as inverted pairs, they function to stall replication forks; and when recombination machinery is subsequently recruited to these stalled forks, the dispersed Ty1 elements provide numerous templates for ectopic repair. Abundant evidence exists for the association of Ty1 sequences with chromosomal translocations that may result from ectopic recombination in industrial, laboratory, and evolutionary settings. Most notably, strains evolved under nutrient limitation contained chromosomal translocation breakpoints largely coincident with Ty1 elements.
A recent paper describes a set of yeast strains with Ty1 copy numbers as many as 10 times that of the WT strain. This increased Ty1 content not only promotes genome instability, but further enables the identification of genes and pathways that contribute to the suppression of retrotransposon-mediated instability. The paper shows that increasing retrotransposon abundance is detrimental to the fitness and stability of the yeast genome, even in the absence of ongoing retrotransposition. The ability of higher eukaryotic cells to maintain levels of repetitive DNA at much higher levels than in yeast cells underscores the importance of highly efficient and precisely controlled DNA replication and error prevention machinery to safeguard against the deleterious potential of such expansion. Yet the persistence of retrotransposon DNA, despite the inherent risk posed by its maintenance, suggests that the resulting genome alterations confer an important and ongoing underlying evolutionary benefit to cells, driving adaptation and evolution of the genome.
Retrotransposon overdose and genome integrity. PNAS USA August 4, 2009. doi: 10.1073/pnas.0906552106
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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Tags: Biology, Genetics, Medicine, Microbiology, Retrotransposon, Science, Virology, virus
