Toxicity and lifespan extension

Histone synthesis is highly regulated in all eukaryotes, and has served as a paradigm for understanding cell cycle regulated-transcription,1 post-transcriptional RNA processing,2 and regulated protein decay.3 Improper histone expression can have deleterious effects on cell-cycle progression,4 chromosome stability5 and gene expression.6 Two recent papers show there are many other effects, describing new phenotypes associated with histone overexpression in budding yeast. In previous experiments, Akash Gunjan and coworkers observed that budding yeast cells lacking checkpoint kinase Rad53 are very sensitive to histone overexpression. This lead to the discovery Rad53 has a novel, non-checkpoint related role in degradation of excess soluble histones.3 Specifically, histone phosphorylation by Rad53 triggers proteosome-mediated degradation.7 In a previous issue of Cell Cycle, this laboratory explored multiple ways in which excess histones affect cells. Multiple effects are observed: yeast mutants lacking several different histone modifying enzyme subunits are shown to be sensitive to histone H3 overexperession, suggesting that excess histones might overload modification pathways. H3 overexpression also results in reduced nucleosomal linker length and altered nucleosome positions in vivo. Upon analysis of steady-state mRNA levels, few genes are altered upon overexpression of H3 alone, a somewhat surprising result given the chromatin structural changes documented above. However, overexpression of an H3/H4 gene pair or all four core histones resulted in > 200 loci with > 2-fold alterations in mRNA levels. Curiously, several clusters of adjacent genes were among these, suggesting that specific chromatin neighborhoods are particularly sensitive to histone density. Perhaps these observations are related to older findings that overexpression of histone pairs but not individual histones causes chromosome loss.5 Finally, the investigators show that excess histones can be crosslinked to RNA in vivo, raising the possibility that excess histones could exert some of their effects via sequestration of RNAs. Those sorts of observations might lead one to predict that histone overexpression would promote reduced viability or shorter lifespans. However, recent work from Jessica Tyler and coworkers8 suggests just the opposite: histone H3/H4 (but not H2A/H2B) overexpression lengthens the budding yeast replicative life-span. Conversely, replicatively old cells display reduced histone levels. These data suggest that depletion of histones during aging could lead to undesirable access to DNA, perhaps via cryptic transcription; in this view, extra histones would offset this loss. How can we consolidate these seemingly contradictory observations that histone overexpression can perturb chromosomes yet still extend lifespan? A comprehensive model would suggest that cells are able to cope with minor perturbations caused by histone overexperssion when they are young (as long as the Rad53-mediated decay pathway is intact, so that grossly toxic occlusion of DNA is avoided). In contrast, in old cells the reduced amount of histones reveals the benefit of a fully packaged genome, such that histone overexpression prevents many of the deleterious effects of age-associated histone loss in old cells. In the future, it will be interesting to determine the extent that the phenomena of kinase-mediated destruction of nascent molecules and age-associated histone loss are conserved in other eukaryotes.