Limits...
A structural basis for cellular senescence.

Aranda-Anzaldo A - Aging (Albany NY) (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Biología Molecular, Facultad de Medicina, Universidad Autónoma del Estado de México, Paseo Tollocan y Jesús Carranza, Toluca, Edo. Méx., México. aaa@uaemex.mx

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.

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Related in: MedlinePlus

A self-stabilizing tensegrity model for DNA-NM interactions in the cell nucleus as a function of age. (A) In a newborn cell NMproteins are in a compacted immature state (brown), thus the NM contactsurface is reduced and so a large DNA loop (black) is anchored to two NMsegments by means of two MARs that became actual LARs (blue circles) whilethree potential MARs (yellow circles) cannot attach to the NM due to sterichindrance and lack of enough contact surface. During mitosis biochemicalmodification of NM proteins (e.g., phosphorylation, red circles) causedisassembly of the NM network leading to disappearance of the cell nucleus.(B) In an adult cell the NM proteins are in a more extended stateoffering a larger contact surface, thus further potential MARs becomeactualized as LARs reducing the average DNA loop size and increasing theDNA-NM interactions. Yet phosphorylation of NM proteins leads to nucleardisassembly during mitosis. (C) In a senescent cell the NM proteinsare fully extended thus offering enough contact surface for severalpotential MARs to become actualized as LARs since steric hindrance isfurther reduced. DNA loops become shorter on average and DNA-NMinteractions are significantly more numerous. Phosphorylation of NMproteins during mitosis cannot lead to nuclear disassembly since theDNA-loops keep separate NM segments bound together and stabilized by meansof the LARs attached to the NM. Thus the available energy becomes limitingfor disassembling the nucleus and the cell cannot enter or perform mitosis.
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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 NMproteins are in a compacted immature state (brown), thus the NM contactsurface is reduced and so a large DNA loop (black) is anchored to two NMsegments by means of two MARs that became actual LARs (blue circles) whilethree potential MARs (yellow circles) cannot attach to the NM due to sterichindrance and lack of enough contact surface. During mitosis biochemicalmodification of NM proteins (e.g., phosphorylation, red circles) causedisassembly of the NM network leading to disappearance of the cell nucleus.(B) In an adult cell the NM proteins are in a more extended stateoffering a larger contact surface, thus further potential MARs becomeactualized as LARs reducing the average DNA loop size and increasing theDNA-NM interactions. Yet phosphorylation of NM proteins leads to nucleardisassembly during mitosis. (C) In a senescent cell the NM proteinsare fully extended thus offering enough contact surface for severalpotential MARs to become actualized as LARs since steric hindrance isfurther reduced. DNA loops become shorter on average and DNA-NMinteractions are significantly more numerous. Phosphorylation of NMproteins during mitosis cannot lead to nuclear disassembly since theDNA-loops keep separate NM segments bound together and stabilized by meansof the LARs attached to the NM. Thus the available energy becomes limitingfor disassembling the nucleus and the cell cannot enter or perform mitosis.

Mentions: From the structuralperspective, the topological organization of higher-order DNA structure basedon selective use of a limited set of potential MARs (as seen in nuclei fromnewborn and baby animals) is highly asymmetrical and the natural trend for mostphysical systems is towards reducing the asymmetries in such a way that thesystem evolves in time so as to become more symmetrical [84-86]. A topologicalconfiguration in which most potential MARs are actually bound to the NM, thusresulting in shorter and more stable DNA loops, is also a more symmetricalstructural attractor. Moreover, since entropy is not a measure of disorder orchaos, but of energy diffusion, dissipation or dispersion in a final statecompared to an initial state [87], such a highly-stable DNA-loop configurationsatisfies the second law of thermodynamics since the structural stress alongthe DNA molecule is more evenly dispersed within the nuclear volume byincreasing the number of DNA-NM interactions (thus increasing, in terms ofmolecular thermodynamics, the occupancy of more microstates in phase space). Alarger number of DNA-NM interactions create a structural complex, similar to ahanging bridge in which beams (proteins) and tensors (DNA) interact forcreating a highly stable overall structure. Thus any relatively stableinteraction between two NM-protein filaments will be further stabilized if agiven DNA loop interacts with both filaments, but also the stability of the DNAloop shall be increased by the interaction with both protein filaments,resulting in a self-reinforcing structural stability that operates at the scaleof the whole interphase nucleus (Figure 1).


A structural basis for cellular senescence.

Aranda-Anzaldo A - Aging (Albany NY) (2009)

A self-stabilizing tensegrity model for DNA-NM interactions in the cell nucleus as a function of age. (A) In a newborn cell NMproteins are in a compacted immature state (brown), thus the NM contactsurface is reduced and so a large DNA loop (black) is anchored to two NMsegments by means of two MARs that became actual LARs (blue circles) whilethree potential MARs (yellow circles) cannot attach to the NM due to sterichindrance and lack of enough contact surface. During mitosis biochemicalmodification of NM proteins (e.g., phosphorylation, red circles) causedisassembly of the NM network leading to disappearance of the cell nucleus.(B) In an adult cell the NM proteins are in a more extended stateoffering a larger contact surface, thus further potential MARs becomeactualized as LARs reducing the average DNA loop size and increasing theDNA-NM interactions. Yet phosphorylation of NM proteins leads to nucleardisassembly during mitosis. (C) In a senescent cell the NM proteinsare fully extended thus offering enough contact surface for severalpotential MARs to become actualized as LARs since steric hindrance isfurther reduced. DNA loops become shorter on average and DNA-NMinteractions are significantly more numerous. Phosphorylation of NMproteins during mitosis cannot lead to nuclear disassembly since theDNA-loops keep separate NM segments bound together and stabilized by meansof the LARs attached to the NM. Thus the available energy becomes limitingfor disassembling the nucleus and the cell cannot enter or perform mitosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2806039&req=5

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 NMproteins are in a compacted immature state (brown), thus the NM contactsurface is reduced and so a large DNA loop (black) is anchored to two NMsegments by means of two MARs that became actual LARs (blue circles) whilethree potential MARs (yellow circles) cannot attach to the NM due to sterichindrance and lack of enough contact surface. During mitosis biochemicalmodification of NM proteins (e.g., phosphorylation, red circles) causedisassembly of the NM network leading to disappearance of the cell nucleus.(B) In an adult cell the NM proteins are in a more extended stateoffering a larger contact surface, thus further potential MARs becomeactualized as LARs reducing the average DNA loop size and increasing theDNA-NM interactions. Yet phosphorylation of NM proteins leads to nucleardisassembly during mitosis. (C) In a senescent cell the NM proteinsare fully extended thus offering enough contact surface for severalpotential MARs to become actualized as LARs since steric hindrance isfurther reduced. DNA loops become shorter on average and DNA-NMinteractions are significantly more numerous. Phosphorylation of NMproteins during mitosis cannot lead to nuclear disassembly since theDNA-loops keep separate NM segments bound together and stabilized by meansof the LARs attached to the NM. Thus the available energy becomes limitingfor disassembling the nucleus and the cell cannot enter or perform mitosis.
Mentions: From the structuralperspective, the topological organization of higher-order DNA structure basedon selective use of a limited set of potential MARs (as seen in nuclei fromnewborn and baby animals) is highly asymmetrical and the natural trend for mostphysical systems is towards reducing the asymmetries in such a way that thesystem evolves in time so as to become more symmetrical [84-86]. A topologicalconfiguration in which most potential MARs are actually bound to the NM, thusresulting in shorter and more stable DNA loops, is also a more symmetricalstructural attractor. Moreover, since entropy is not a measure of disorder orchaos, but of energy diffusion, dissipation or dispersion in a final statecompared to an initial state [87], such a highly-stable DNA-loop configurationsatisfies the second law of thermodynamics since the structural stress alongthe DNA molecule is more evenly dispersed within the nuclear volume byincreasing the number of DNA-NM interactions (thus increasing, in terms ofmolecular thermodynamics, the occupancy of more microstates in phase space). Alarger number of DNA-NM interactions create a structural complex, similar to ahanging bridge in which beams (proteins) and tensors (DNA) interact forcreating a highly stable overall structure. Thus any relatively stableinteraction between two NM-protein filaments will be further stabilized if agiven DNA loop interacts with both filaments, but also the stability of the DNAloop shall be increased by the interaction with both protein filaments,resulting in a self-reinforcing structural stability that operates at the scaleof the whole interphase nucleus (Figure 1).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Biología Molecular, Facultad de Medicina, Universidad Autónoma del Estado de México, Paseo Tollocan y Jesús Carranza, Toluca, Edo. Méx., México. aaa@uaemex.mx

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.

Show MeSH
Related in: MedlinePlus