The adaptive potential of circular DNA accumulation in ageing cells

Ryan M Hull,Jonathan Houseley

doi:10.1007/s00294-020-01069-9

Ryan M Hull, Jonathan Houseley

Open Access

https://doi.org/10.1007/s00294-020-01069-9

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Abstract

Carefully maintained and precisely inherited chromosomal DNA provides long-term genetic stability, but eukaryotic cells facing environmental challenges can benefit from the accumulation of less stable DNA species. Circular DNA molecules lacking centromeres segregate randomly or asymmetrically during cell division, following non-Mendelian inheritance patterns that result in high copy number instability and massive heterogeneity across populations. Such circular DNA species, variously known as extrachromosomal circular DNA (eccDNA), microDNA, double minutes or extrachromosomal DNA (ecDNA), are becoming recognised as a major source of the genetic variation exploited by cancer cells and pathogenic eukaryotes to acquire drug resistance. In budding yeast, circular DNA molecules derived from the ribosomal DNA (ERCs) have been long known to accumulate with age, but it is now clear that aged yeast also accumulate other high-copy protein-coding circular DNAs acquired through both random and environmentally-stimulated recombination processes. Here, we argue that accumulation of circular DNA provides a reservoir of heterogeneous genetic material that can allow rapid adaptation of aged cells to environmental insults, but avoids the negative fitness impacts on normal growth of unsolicited gene amplification in the young population.

Highlights

From a human perspective, the concept of mutation appears purely negative, associated only with degeneration and cancer
It is well understood that prokaryotes supplement chromosomal genetic material with circular DNA plasmids that deviate from normal rules of Mendelian inheritance and accelerate adaptation
We examine the potential of circular DNA to accelerate adaptation in eukaryotes in general and ask whether the accumulation of particular circular DNA species during ageing in yeast enhances the potential of those species to confer adaptive phenotypes, providing a beneficial outcome of ageing in simple eukaryotes

Summary

Introduction

The concept of mutation appears purely negative, associated only with degeneration and cancer. Many circular DNA species do not form at a high rate, nor contain active replication origins and, the copy number of these species in mother cells will remain static or decrease with age.

Results

Conclusion