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.

The post-mitotic state in neurons correlates with a stable nuclear higher-order structure

“…A corollary is that not all potential MARs present in DNA are actually attached to the NM. The interactions between DNA and the NM define a higher-order structure (NHOS) in the interphase nucleus 36 , 37 …”

“…Yet such interactions increase in strength and number as a function of time so that DNA loops become shorter on average and more homogeneous in size as a function of age and this correlates with the loss of proliferating potential 57 . Based on such evidence the hypothesis was put forward that SRS has a structural, non-genetic basis resulting from thermodynamic constraints acting upon DNA that lead to an ever increasing number of DNA-NM interactions in order to dissipate DNA structural stress 36 . Therefore DNA loops become shorter, more numerous and more homogeneous in size as a function of time.…”

The organization of a large transcriptional unit (Fyn) into structural DNA loops is cell-type specific and independent of transcription

“…Therefore, not all potential MARs are actually bound to the NM constituting LARs. Indeed the DNA-NM interactions define a higher-order structure within the cell nucleus (Aranda-Anzaldo, 2009). The current evidence indicates that DNA replication, transcription and processing of primary transcripts occur at macromolecular complexes or factories organized upon the NM (Anachkova et al, 2005;Berezney and Wei, 1998;Cook, 1999).…”

Aged and post-mitotic cells share a very stable higher-order structure in the cell nucleus in vivo

“…The spontaneous, permanent cellcycle arrest observed in primary cells and the postmitotic state characteristic of early, terminallydifferentiated cells such as neurons, are remarkably stable and compatible with long-term cell survival. Both states seem to be non-reversible and so independent of soluble regulatory factors acting in trans, suggesting that there might be a common factor linking both cellular states (Aranda-Anzaldo, 2009). …”