Abstract
Extrachromosomal circular DNA (eccDNA) facilitates adaptive evolution by allowing rapid and extensive gene copy number variation and is implicated in the pathology of cancer and ageing. Here, we demonstrate that yeast aged under environmental copper accumulate high levels of eccDNA containing the copper-resistance gene CUP1. Transcription of the tandemly repeated CUP1 gene causes CUP1 eccDNA accumulation, which occurs in the absence of phenotypic selection. We have developed a sensitive and quantitative eccDNA sequencing pipeline that reveals CUP1 eccDNA accumulation on copper exposure to be exquisitely site specific, with no other detectable changes across the eccDNA complement. eccDNA forms de novo from the CUP1 locus through processing of DNA double-strand breaks (DSBs) by Sae2, Mre11 and Mus81, and genome-wide analyses show that other protein coding eccDNA species in aged yeast share a similar biogenesis pathway. Although abundant, we find that CUP1 eccDNA does not replicate efficiently, and high-copy numbers in aged cells arise through frequent formation events combined with asymmetric DNA segregation. The transcriptional stimulation of CUP1 eccDNA formation shows that age-linked genetic change varies with transcription pattern, resulting in gene copy number profiles tailored by environment.
Highlights
In contrast to the normally sedate evolution of chromosomal DNA, extrachromosomal circular DNA can be rapidly accumulated and lost in eukaryotic cells, facilitating timely changes in gene expression and accelerating adaptation. eccDNA accumulation provides a pathway for adapting to drug treatment, environmental stress, and genetic deficiency in diverse eukaryotes [1,2,3,4,5]
extrachromosomal ribosomal DNA circle (ERC) are enriched in aged yeast, and we speculated that other eccDNA may be enriched during ageing
We found that cells lacking the SAGA component Spt3 contain far less CUP1 eccDNA and ERCs after 24 hours (Fig 3A and 3B), even though transcriptional induction of the CUP1 promoter was normal in spt3Δ cells (S3 Fig)
Summary
In contrast to the normally sedate evolution of chromosomal DNA, extrachromosomal circular DNA (eccDNA) can be rapidly accumulated and lost in eukaryotic cells, facilitating timely changes in gene expression and accelerating adaptation. eccDNA accumulation provides a pathway for adapting to drug treatment, environmental stress, and genetic deficiency in diverse eukaryotes [1,2,3,4,5]. EccDNA accumulation provides a pathway for adapting to drug treatment, environmental stress, and genetic deficiency in diverse eukaryotes [1,2,3,4,5]. In contrast to the normally sedate evolution of chromosomal DNA, extrachromosomal circular DNA (eccDNA) can be rapidly accumulated and lost in eukaryotic cells, facilitating timely changes in gene expression and accelerating adaptation. Amplification of both driving oncogenes and chemotherapy.
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