- #LAMIN B ASSOCIATION WITH DNA REPAIR FACTORS DRIVERS#
- #LAMIN B ASSOCIATION WITH DNA REPAIR FACTORS SKIN#
#LAMIN B ASSOCIATION WITH DNA REPAIR FACTORS DRIVERS#
Recent studies showed that epigenetic systems could play an active role as drivers of both forms of aging. Multiple epigenetic changes are common to premature aging in HGPS and natural aging. The chronological aging in normal individuals and the premature aging in HGPS patients are mediated by similar changes in the activity of signaling pathways, including downregulation of DNA repair and chromatin organization, and upregulation of ERK, mTOR, GH-IGF1, MAPK, TGFβ, and mitochondrial dysfunction. Changes in lamina organization may directly affect telomere attrition resulting in accelerated replicative senescence and progeroid phenotypes. Progerin expression in normal human fibroblasts accelerates the loss of telomeres. Telomere attrition is widely regarded to be one of the primary hallmarks of aging. Excessive activity of the same mechanisms may well be the cause of premature aging in HGPS.
Thus, progerin-dependent mechanisms act in natural aging. Inhibition of progerin production in cells of aged non-HGPS donors in vivo increases the proliferative activity, H3K9me3, and HP1, and decreases the senescence markers p21, IGFBP3, and GADD45B to the levels of young donor cells. These cells display HGPS-like defects in nuclear morphology, decreased H3K9me3 and HP1, and increased histone H2AX phosphorylation marks of the DNA damage loci.
#LAMIN B ASSOCIATION WITH DNA REPAIR FACTORS SKIN#
Progerin-positive cells are present in primary fibroblast cultures obtained from the skin of normal donors at advanced ages. Progerin acts as a dominant factor that leads to multiple morphological anomalies of cell nuclei and disturbances in heterochromatin organization, mitosis, DNA replication and repair, and gene transcription. The Hutchinson–Gilford progeria syndrome (HGPS) is a premature aging disease caused by mutations of the LMNA gene leading to increased production of a partially processed form of the nuclear fibrillar protein lamin A – progerin. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
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