Abstract
Aging, the universal phenomenon, affects human health and is the primary risk factor for major disease pathologies. Progeroid diseases, which mimic aging at an accelerated rate, have provided cues in understanding the hallmarks of aging. Mutations in DNA repair genes as well as in telomerase subunits are known to cause progeroid syndromes. Werner syndrome (WS), which is characterized by accelerated aging, is an autosomal-recessive genetic disorder. Hallmarks that define the aging process include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulation of nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. WS recapitulates these hallmarks of aging and shows increased incidence and early onset of specific cancers. Genome integrity and stability ensure the normal functioning of the cell and are mainly guarded by the DNA repair machinery and telomeres. WRN, being a RecQ helicase, protects genome stability by regulating DNA repair pathways and telomeres. Recent advances in WS research have elucidated WRN’s role in DNA repair pathway choice regulation, telomere maintenance, resolution of complex DNA structures, epigenetic regulation, and stem cell maintenance.
Highlights
Werner syndrome (WS) is a segmental progeria
Patients with WS suffer from severe intractable foot ulcers; the underlying pathology has yet to be understood
Age-associated cataracts occur because of an imbalance in the proteostasis in the lens cells[94]; perhaps a similar mechanism is at play in WS
Summary
Werner syndrome (WS) is a segmental progeria. It belongs to a small group of disorders characterized by accelerated aging. Increased DNA damage accumulation, genomic instability, telomere attrition, and histone methylation are contributing factors for cellular senescence and stem cell exhaustion in WS13,14. We discuss some areas of particular relevance where significant insight has been gathered in recent years These include the role of WRN in DNA double-strand break (DSB) repair, telomere maintenance, senescence and heterochromatin stabilization, and cancer. The liver is considered a regenerative organ and may have the capacity to re-activate telomerase in this tissue, negating the impact of WRN loss In another recent study, younger WS patients with intractable ulcers had normal terminal restriction fragment lengths, suggesting that telomere length was not likely driving this phenotype[10]. Cellular senescence in WRN-deficient cells was believed to be due to telomere issues and the accumulation of replication-associated endogenous DNA damage. It is possible that WRN expression or degradation (or both) could be used as a biomarker for personalized chemotherapy, and further research should explore this potential
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