Selective benefits of damage partitioning in unicellular systems and its effects on aging

Abstract

Cytokinesis in unicellular organisms sometimes entails a division of labor between cells leading to lineage-specific aging. To investigate the potential benefits of asymmetrical cytokinesis, we created a mathematical model to simulate the robustness and fitness of dividing systems displaying different degrees of damage segregation and size asymmetries. The model suggests that systems dividing asymmetrically (size-wise) or displaying damage segregation can withstand higher degrees of damage before entering clonal senescence. When considering population fitness, a system producing different-sized progeny like budding yeast is predicted to benefit from damage retention only at high damage propagation rates. In contrast, the fitness of a system of equal-sized progeny is enhanced by damage segregation regardless of damage propagation rates, suggesting that damage partitioning may also provide an evolutionary advantage in systems dividing by binary fission. Indeed, by using Schizosaccharomyces pombe as a model, we experimentally demonstrate that damaged proteins are unevenly partitioned during cytokinesis and the damage-enriched sibling suffers from a prolonged generation time and accelerated aging. This damage retention in S. pombe is, like in Saccharomyces cerevisiae, Sir2p-and cytoskeleton-dependent, suggesting this to be an evolutionarily conserved mechanism. We suggest that sibling-specific aging may be a result of the strong selective advantage of damage segregation, which may be more common in nature than previously anticipated.computational modeling ͉ protein damage ͉ fitness ͉ asymmetry

Spatial protein quality control and the evolution of lineage-specific ageing

“…Intriguingly, SQC is not unique for cells dividing by budding, but also operates in the fission yeast, Schizosaccharomyces pombe, and is cytoskeleton-(both F-actin and microtubules), polarisome-(Tea1) and sirtuin-dependent [20,23]. This gives rise to a damage-enriched and a damage-free cell lineage despite the fact that cytokinesis is accomplished by binary fission [23].…”

“…Thus, mutants with a crippled SQC are not, in this model, predicted to enter clonal senescence as long as the production of damage is relatively low. Indeed, wild-type and sir2 mutant populations of S. pombe display the same fitness (growth rate) when cultured without stressors but hydrogen peroxide causes a much more pronounced fitness reduction in sir2 mutants (lacking damage segregation) than wild-type cells [23].…”

“…Also, it is possible that upon elevated external stresses reaching lethal levels, an asymmetrical segregation of irreparable damage may permit survival of the clone at the expense of the 'mother-type' cells. Indeed, a mathematical model created to simulate the robustness and fitness of dividing systems displaying different degrees of damage segregation and size asymmetries indicated that systems dividing asymmetrically (size-wise) or displaying damage segregation withstand higher degrees of damage [23]. However, the model of Erjavec et al [23] also suggests that damage retention may be a mixed blessing; it raises the upper limits for how much damage the system can endure before entering clonal senescence but becomes a selective disadvantage at low damage production rates.…”

“…Indeed, a mathematical model created to simulate the robustness and fitness of dividing systems displaying different degrees of damage segregation and size asymmetries indicated that systems dividing asymmetrically (size-wise) or displaying damage segregation withstand higher degrees of damage [23]. However, the model of Erjavec et al [23] also suggests that damage retention may be a mixed blessing; it raises the upper limits for how much damage the system can endure before entering clonal senescence but becomes a selective disadvantage at low damage production rates. Thus, mutants with a crippled SQC are not, in this model, predicted to enter clonal senescence as long as the production of damage is relatively low.…”

“…A genetic screen, using Saccharomyces cerevisiae, identified the protein Sir2p as a required component in retaining damage in the ageing mother cell [19,20,22,23]. Sir2p, the founding father of the family of sirtuins, is a conserved nicotinamide adenine dinucleotide-dependent protein (histone) deacetylase, shown to act as a modulator of ageing in a variety of organisms, including yeast, worms, flies, fish and mammals [24 -27].…”