A structural basis for cellular senescence

Abstract

Replicative senescence (RS) that limits the proliferating potential of normal eukaryotic cells occurs either by a cell-division counting mechanism linked to telomere erosion or prematurely through induction by cell stressors such as oncogene hyper-activation. However, there is evidence that RS also occurs by a stochastic process that is independent of number of cell divisions or cellular stress and yet it leads to a highly-stable, non-reversible post-mitotic state that may be long-lasting and that such a process is widely represented among higher eukaryotes. Here I present and discuss evidence that the interactions between DNA and the nuclear substructure, commonly known as the nuclear matrix, define a higher-order structure within the cell nucleus that following thermodynamic constraints, stochastically evolves towards maximum stability, thus becoming limiting for mitosis to occur. It is suggested that this process is responsible for ultimate replicative senescence and yet it is compatible with long-term cell survival.

Keywords: DNA loops; TOR; hepatocytes; matrix attachment regions; nuclear matrix; tensegrity.

Figure 1.. A self-stabilizing tensegrity model for DNA-NM interactions in the cell nucleus as a function of age.

(A) In a newborn cell NM proteins are in a compacted immature state (brown), thus the NM contact surface is reduced and so a large DNA loop (black) is anchored to two NM segments by means of two MARs that became actual LARs (blue circles) while three potential MARs (yellow circles) cannot attach to the NM due to steric hindrance and lack of enough contact surface. During mitosis biochemical modification of NM proteins (e.g., phosphorylation, red circles) cause disassembly of the NM network leading to disappearance of the cell nucleus. (B) In an adult cell the NM proteins are in a more extended state offering a larger contact surface, thus further potential MARs become actualized as LARs reducing the average DNA loop size and increasing the DNA-NM interactions. Yet phosphorylation of NM proteins leads to nuclear disassembly during mitosis. (C) In a senescent cell the NM proteins are fully extended thus offering enough contact surface for several potential MARs to become actualized as LARs since steric hindrance is further reduced. DNA loops become shorter on average and DNA-NM interactions are significantly more numerous. Phosphorylation of NM proteins during mitosis cannot lead to nuclear disassembly since the DNA-loops keep separate NM segments bound together and stabilized by means of the LARs attached to the NM. Thus the available energy becomes limiting for disassembling the nucleus and the cell cannot enter or perform mitosis.