Chromatin remodeling may enforce cell senescence
Karl Riabowol
Southern Alberta Cancer Research Institute, University of Calgary Health Sciences Centre, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1
Normal human cells that divide in culture undergo a limited number of
populations doublings commonly referred to as the Hayflick limit.
Mammalian tissues that normally replicate, acquire increasing
proportions of cells that cannot divide and that are in a state of
replicative senescence. Mounting evidence indicates that the rate at
which these populations of cells accumulate contributes to determining
biological lifespan. Many stresses contribute to limiting replicative
lifespan. Even in the absence of external stresses such as radiation
or severe oxidative damage that result in stress-induced premature
senescence, the erosion of telomeres to a critical length due to the
end replication problem imposes a maximum lifespan potential on cells.
Signals initiated by short telomeres that may resemble DNA damage are
initially sensed, and then transduced, by divergent pathways to a set
of tumour suppressors that integrate damage signals to determine their
effects upon chromatin structure. During the final stages of
senescence, when the state becomes virtually irreversible, chromatin
structure changes dramatically, affecting DNA distribution and density
as indicated by the formation of senescence-associated heterochromatic
foci (SAHF) and altered gene expression. Several genes in the p53, Rb
and ING pathways are affected, with increased expression of both ING1
and ING2 leading to the activation of a Factor Acetyl Transferase (FAT)
that activates p53 and a Histone Deacetylase (HDAC1) complex. These
events induce expression of the p16 and p21 cyclin dependent kinase
inhibitors that inhibit cell growth and inhibit growth stimulatory
genes, maintaining cells in a state of replicative senescence through
the coordinated alteration of chromatin structure.
Key words:
senescence, ING1, chromatin, acetylation, stress
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