April 22, 2022
Replicative lifespan (RLS), determined by the number of daughter cells a mother cell produces before death, has proved to be an effective model for studying aging in budding yeast. The chromatin-associated proteins Sir2p and Fob1p have been shown to modulate ribosomal DNA (rDNA) and impact the formation of extrachromosomal rDNA circles (ERCs), an accumulation of which is linked to a shorter lifespan.
A recent study by Hotz M et al. in PNAS has shown that chromosomal rDNA copy number (CN) positively correlates with RLS in budding yeast. The authors performed whole-genome sequencing (WGS) of 13 wild-type strains and analyzed the lifespan data, which showed an increased rDNA CN along with enhanced RLS. Additionally, the data showed that the rDNA CN explains the majority (~ 70%) of RLS variation observed in almost identical wild-type strains.
To understand this correlation, the authors analyzed ERC levels in aging cells and fob1-Δ strains, in which ERC levels are low. Together, the analysis concluded that ERCs are inversely correlated with rDNA CN. Exploring further, the authors found that cells with lower rDNA CN showed improved accessibility of the upstream activating factor (UAF) complex binding site at the SIR2 locus. This change in chromatin accessibility reduces the expression of SIR2, causing higher ERC levels and thus a shortened lifespan, implicating both Sir2p levels and ERCs as the underlying cause of the CN-RLS correlation.
Additionally, the authors analyzed the CN-RLS relationship in a set of mutant strains (such as hda2-Δ, upb8-Δ, gpa2-Δ, etc.), all known to increase lifespan. The data showed that while some mutants appeared to impact the CN-RLS relationship, rDNA CN strongly influenced the RLS of these mutant strains (except for fob1-Δ).
Thus, the study demonstrates how rDNA CN impacts yeast lifespan by regulating certain aging factors and highlights rDNA copy number as an essential parameter to examine in aging studies.
Categories: Research Spotlight