Abstract
Circular DNA can arise from all parts of eukaryotic chromosomes. In yeast, circular ribosomal DNA (rDNA) accumulates dramatically as cells age, however little is known about the accumulation of other chromosome-derived circles or the contribution of such circles to genetic variation in aged cells. We profiled circular DNA in Saccharomyces cerevisiae populations sampled when young and after extensive aging. Young cells possessed highly diverse circular DNA populations but 94% of the circular DNA were lost after ∼15 divisions, whereas rDNA circles underwent massive accumulation to >95% of circular DNA. Circles present in both young and old cells were characterized by replication origins including circles from unique regions of the genome and repetitive regions: rDNA and telomeric Y’ regions. We further observed that circles can have flexible inheritance patterns: [HXT6/7circle] normally segregates to mother cells but in low glucose is present in up to 50% of cells, the majority of which must have inherited this circle from their mother. Interestingly, [HXT6/7circle] cells are eventually replaced by cells carrying stable chromosomal HXT6 HXT6/7 HXT7 amplifications, suggesting circular DNAs are intermediates in chromosomal amplifications. In conclusion, the heterogeneity of circular DNA offers flexibility in adaptation, but this heterogeneity is remarkably diminished with age.
Highlights
In the unicellular eukaryote Saccharomyces cerevisiae, aging is determined by the number of divisions a mother cell undergoes before losing the ability to replicate [1]
We further observed that circles can have flexible inheritance patterns: [HXT6/7circle] normally segregates to mother cells but in low glucose is present in up to 50% of cells, the majority of which must have inherited this circle from their mother
We found that most circular DNAs are lost from aging cells, while circular DNA with replication origins are prone to be maintained in cells as they age but only a few of these circular DNAs accumulate in aging cells
Summary
In the unicellular eukaryote Saccharomyces cerevisiae, aging is determined by the number of divisions a mother cell undergoes before losing the ability to replicate [1]. Replicative aging is not associated with circular DNA from the rDNA locus but rather the accumulation of circular DNA in general causes a shorter lifespan of the mother cell [4]. Our knowledge about segregation of other circular DNA species of chromosomal origin is based on a few model circles with a small range of genetic markers [4,6,7,11]. It is not clear whether segregation kinetics, inferred from a small number of model circles, can be generalized to circular DNA formed from other parts of the genome. The segregation kinetics is important to establish since circular DNA derived from other parts of the genome might naturally contribute to aging, and because amplification of genes on circular DNA can have strong phenotypic effects on the host cell [12,13,14,15,16]
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