The adaptive potential of circular DNA accumulation in ageing cells
- PDF / 662,057 Bytes
- 6 Pages / 595.276 x 790.866 pts Page_size
- 26 Downloads / 159 Views
MINI-REVIEW
The adaptive potential of circular DNA accumulation in ageing cells Ryan M. Hull1 · Jonathan Houseley2 Received: 20 February 2020 / Revised: 12 March 2020 / Accepted: 14 March 2020 © The Author(s) 2020
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 proteincoding 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. Keywords Circular DNA · Extrachromosomal DNA · Double minutes · Extrachromosomal circular DNA · Ageing · NonMendelian inheritance From a human perspective, the concept of mutation appears purely negative, associated only with degeneration and cancer. However, all living organisms must maintain an appropriate mutation rate to survive: too high a rate leads to genome instability and degradation of vital functions, but conversely too little mutation strangles evolution by suppressing genetic diversity, preventing adaptation to new environmental challenges and condemning an organism to be out-competed. Evolutionary studies in E. coli and asexual yeasts reveal that strains with high mutation rates outperform those with low mutation rates, showing that mutation provides an adaptive advantage (Arjan et al. 1999; Desai et al. 2007; Wielgoss et al. 2013). However, increasing the
Communicated by M. Kupiec. * Jonathan Houseley [email protected] 1
SciLifeLab, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden
Epigenetics Programme, The Babraham Institute, Cambridge, UK
2
mutation rate only improves adaptability up to a critical “error threshold”: above this, further increases reduce adaptability because fitness-enhancing mutations only account for a very small proportion of total mutations, and the accumulation of more frequent deleterious mutations becomes limiting for fitness (Eyre-Walker and Keightley 2007; Gerrish et al. 2013;
Data Loading...
