Researchers from the Houseley lab have challenged the existing theory of what causes ageing yeast cells to enter a senescent state where they lose fitness and show many signs of pathology. Instead of blaming the long-recognised accumulation of circular DNA within cells, they suggest that formation of chromosome fragments cause cells to malfunction. Given the common machinery and functions shared between yeast cells and cells of humans, it is possible that their results could identify a common cause for ageing on the molecular level.
“DNA circles as the cause of ageing in yeast was a nice theory, but the mechanism isn't shared across species. By contrast, the aberrant DNA fragments we have identified might cause pathology in ways which are more similar between yeast and mammals.” said Dr Andre Zylstra, lead author on the paper.
For over twenty years researchers have suspected that yeast cell lifespan is limited by the accumulation of huge amounts of seemingly useless circular DNA. This DNA was thought to slowly overwhelm cellular systems leading to cause senescence. However, circular DNA does not accumulate with age in other organisms. While investigating the presence of different types of DNA in yeast, the Houseley lab were able to identify new culprits for causing the pathologies of ageing.
“We were surprised to find that senescence, when cells no longer divide, occurs even in yeast mutants which lack circular DNA. This indicates that circular DNAs do not cause senescence, so we then turned our eye to other genome changes that accompany ageing in yeast.” Explained Dr Jon Houseley, Group leader in the Epigenetics research programme.
The team examined aged mutant cells that don’t accumulate circular DNA during ageing to find an alternative explanation for the onset of senescence. They identified a chromosomal fragment formed by breakage of yeast chromosome XII that was always present when cells underwent ageing pathology but was absent in healthy ageing cells. Although much less abundant that the circular DNA, this chromosomal fragment appears to be much more toxic.
Whereas accumulation of circular DNA does not occur during ageing outside yeast, there is plenty of evidence for the gain or loss of whole or partial chromosomes, called aneuploidy, as we age. The importance of this aneuploidy is not understood, but our yeast findings suggest it could be a major contributor to the ageing process in humans.
Zylstra, A., et al., Senescence in yeast is associated with amplified linear fragments of chromosome XII rather than ribosomal DNA circle accumulation, PLOS Biology
Honor Pollard, Communications Officer, email@example.com
Image description: Computer generated depiction of budding yeast.
Institute affiliated authors (in author order):
Andre Zylstra, former PhD student, Houseley lab
Hanane Hadj-Moussa, Postdoctoral research scientist, Houseley lab
Dorottya Horkai, former postdoctoral research scientist, Houseley lab
Alex Whale, Postdoctoral research scientist, Houseley lab
Baptiste Piguet, Visiting student, Samant lab
Jonathan Houseley, Group leader, Epigenetics research programme
This research was funded by the Wellcome Trust and the Biotechnology and Biological Sciences Research Council (BBSRC), part of UKRI.
About the Babraham Institute
The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, through Institute Strategic Programme Grants and an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.
The Biotechnology and Biological Sciences Research Council (BBSRC) is part of UK Research and Innovation, a non-departmental public body funded by a grant-in-aid from the UK government. BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.
Funded by government, BBSRC invested £451 million in world-class bioscience in 2019-20. We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.
29 August 2023