Deficiencies in DNA Damage Recognition and Repair in HGPS Cells:
Progeria causes chromatin perturbations, which result in the formation of DSBs (double-strand breaks) and abnormal DDR (DNA-damage response). Progerin may disrupt DDR pathways in HGPS cells. Progerin accumulation results in disruption of functions of some replication and repair factors, causing the mislocalization of XPA protein to the replication forks, replication fork stalling and, subsequently, DNA DSBs. The binding of XPA to the stalled forks excludes normal binding by repair proteins, leading to DSB accumulation, which actives ATM and ATR checkpoints, and arresting cell-cycle progression.
As mutant lamin proteins ...view middle of the document...
" XPA depletion reduces the level of DSBs in HGPS cells. Therefore, XPA binding to DNA DSBs in progeroid cells causes an absence of repair proteins at DNA damage sites and an increase of genome instability due to failure of DNA repair.
DNA damage is mediated by wild-type NER protein XPA, which is trapped to DSB sites. This blocks the access of DSBs to DSB repair factors but also abolishes NER to which XPA belongs. This protein from one DNA repair pathway disrupts another DNA repair pathway.
Clinical Features of HGPS:
Typically, children born with HGPS are seemingly healthy at birth. However, within just a year, they begin to display the phenotypes of accelerated aging. Just as in the mouse knockout of the Zmpste24 enzyme, children with HGPS suffer from growth retardation, cardiac dysfunction, alopecia, and nuclear abnormalities. The most noticeable phenotypes typical of HGPS are wrinkled, aged skin due to the lack of subcutaneous fat, alopecia, and craniofacial disproportion. Other facial features include prominent eyes and scalp veins and micrognathia. Patients diagnosed with HGPS are also subjected to delayed dentitions, high-pitched voices, pyriform thoraxes, and short statures.
Deficiencies in the basic cellular processes (Cell proliferation, differentiation, and gene expression) affect the skin, bone, and cardiovascular tissues. These deficiencies create complications such as cardiovascular disease, particularly arteriosclerotic disease, osteoporosis, and soft tissue...