A structural basis for cellular senescence

Replicativesenescence (RS) that limits the proliferating potential of normaleukaryotic cells occurs either by a cell-division counting mechanism linkedto telomere erosion or prematurely through induction by cell stressors suchas oncogene hyper-activation. However, there is evidence that RS alsooccurs by a stochastic process that is independent of number of celldivisions or cellular stress and yet it leads to a highly-stable,non-reversible post-mitotic state that may be long-lasting and that such aprocess is widely represented among higher eukaryotes. Here I present anddiscuss evidence that the interactions between DNA and the nuclearsubstructure, commonly known as the nuclear matrix, define a higher-orderstructure within the cell nucleus that following thermodynamic constraints,stochastically evolves towards maximum stability, thus becoming limitingfor mitosis to occur. It is suggested that this process is responsible forultimate replicative senescence and yet it is compatible with long-termcell survival.