Some defects in DNA replication and/or repair cause accelerated ageing disorders (Progerias). Indeed, almost all Progeria syndromes are caused by mutations in proteins that directly or indirectly affect DNA metabolism. This may suggest that the progressive accumulation of mutations promotes ageing, although it appears that not all DNA damage causes ageing, and at least in yeast ageing occurs with absolutely no new mutations forming in the heritable chromosomal genome.
Ageing in yeast has long been thought to be driven by accumulation of circular DNAs that are formed as aberrant processing intermediates arising during repair of stalled replication forks in the ribosomal DNA. These are known as extrachromosomal ribosomal DNA circles or ERCs. However, in a comprehensive analysis of mutants rad52Δ and spt3Δ which do not accumulate ERCS, we observed no effect whatsoever on ageing phenotype or gene expression pattern during ageing.
For example, using Principal Component Analysis to cluster genome-wide RNA sequencing data from young and old cells we see that gene expression in these mutants changes with age just as in the wild type.
Instead, using mathematical modelling of large gene expression datasets, we associated the onset of senescence in yeast with accumulation of a cleaved chromosomal fragment called ChrXIIr arising from damage in the ribosomal DNA. On the left is a plot of senescence versus the level of ChrXIIr across age in the different mutants, on the right is an equivalent plot comparing senescence to ERC levels – there is only a correlation for ChrXIIr.
Senescence in yeast is associated with amplified linear fragments of chromosome XII rather than ribosomal DNA circle accumulation Zylstra et al
We hypothesise that the ribosomal DNA, which is the most conserved part of eukaryotic genomes, is particularly important in ageing and that unrepaired DNA damage specifically in the ribosomal DNA disturbs cellular function.
We have developed a suite of bespoke DNA sequencing methods to probe the links between DNA changes and ageing in yeast and mammalian cells, allowing us to detect extremely rare heterogeneous DNA damage occurring through life in particular populations of cells. These methods provide tools to dissect the role of DNA damage in ageing eukaryotic cells.
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