Abstract
BackgroundMutations accumulate as a result of DNA damage and imperfect DNA repair machinery. In higher eukaryotes the accumulation and spread of mutations is limited in two primary ways: through p53-mediated programmed cell death and cellular senescence mediated by telomeres. Telomeres shorten at every cell division and cell stops dividing once the shortest telomere reaches a critical length. It has been shown that the rate of telomere attrition is accelerated when cells are exposed to DNA damaging agents. However the implications of this mechanism are not fully understood.ResultsWith the help of in silico model we investigate the effect of genotoxic stress on telomere attrition and apoptosis in a population of non-identical replicating cells. When comparing the populations of cells with constant vs. stress-induced rate of telomere shortening we find that stress induced telomere shortening (SITS) increases longevity while reducing mutation rate. Interestingly, however, the effect takes place only when genotoxic stresses (e.g. reactive oxygen species due to metabolic activity) are distributed non-equally among cells.ConclusionsOur results for the first time show how non-equal distribution of metabolic load (and associated genotoxic stresses) combined with stress induced telomere shortening can delay aging and minimize mutations.
Highlights
Mutations accumulate as a result of DNA damage and imperfect DNA repair machinery
stress induced telomere shortening (SITS) increases longevity while minimizing mutation rate In Figure 2 we show the dynamics of the three main characteristics: Number of dividing cells in population, N, telomere length, T and number of mutations, M averaged over all cells
Both the increase in longevity and decrease in mutation rate are late events that take place when population of cells approaches a critical length in their telomeres
Summary
Mutations accumulate as a result of DNA damage and imperfect DNA repair machinery. In higher eukaryotes the accumulation and spread of mutations is limited in two primary ways: through p53-mediated programmed cell death and cellular senescence mediated by telomeres. There exist two main ways to limit mutation accumulation in the population of cells: a) eliminate damaged cells or b) set a limit on the number of replications a cell can undergo. In the former case, a severely damaged cell can be removed form the pool of replicating cells in many ways: it can undergo cell-cycle arrest, autophagy, necrosis or activate pre-programmed suicidal program – In an alternative scenario b) the spread of mutations in a lineage of proliferated cells is limited by telomeres and happens on the time-scale of weeks. Once the shortest telomere reaches the critical length (e.g. of about [8] 2000 bp in human fibrobasts), cells undergo replicative senescence – they stop dividing and in some cases undergo apoptosis
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