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Review
. 2017 Sep 28:6:1779.
doi: 10.12688/f1000research.12110.1. eCollection 2017.

Recent Advances in Understanding Werner Syndrome

Raghavendra A Shamanna  1 , Deborah L Croteau  1 , Jong-Hyuk Lee  1 , Vilhelm A Bohr  1
Affiliations
Review

Recent Advances in Understanding Werner Syndrome

Raghavendra A Shamanna et al. F1000Res. .

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.

Keywords: Aging; DSB repair; Senescence; Telomere maintenance; WRN; Werner Syndrome.

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Conflict of interest statement

Competing interests: The authors declare that they have no competing interests.No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.

Figures

Figure 1.
Figure 1.. Double-strand break (DSB) repair pathway choice.
DSBs generated by extrinsic and intrinsic factors are recognized by the sensor proteins Ku70/Ku80, WRN, MRN, and PARP1 to mediate repair. DSBs are repaired via classical/canonical non-homologous end joining (c-NHEJ), alternative (alt)-NHEJ, and homologous recombination (HR) pathways. WRN promotes Ku-dependent c-NHEJ with its catalytic activities and strongly inhibits alt-NHEJ with its non-catalytic activities. WRN suppresses the recruitment and downstream functions of MRE11 and CtIP to inhibit alt-NHEJ. During S/G 2 phases of the cell cycle, WRN promotes HR. Accurate repair of DSBs is required for genome stability without loss of genetic information.
Figure 2.
Figure 2.. The role of WRN in the contexts of the known hallmarks of aging .
The widths of the lines showing inhibition indicate the estimated relative involvement of WRN in the processes. ROS, reactive oxygen species.
See this image and copyright information in PMC

References

    1. Yokote K, Chanprasert S, Lee L, et al. : WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects. Hum Mutat. 2017;38(1):7–15. 10.1002/humu.23128 - DOI - PMC - PubMed

    2. F1000 Recommendation

    1. Masala MV, Scapaticci S, Olivieri C, et al. : Epidemiology and clinical aspects of Werner's syndrome in North Sardinia: description of a cluster. Eur J Dermatol. 2007;17(3):213–6. - PubMed
    1. Nakura J, Wijsman EM, Miki T, et al. : Homozygosity mapping of the Werner syndrome locus (WRN). Genomics. 1994;23(3):600–8. 10.1006/geno.1994.1548 - DOI - PubMed
    1. Takemoto M, Mori S, Kuzuya M, et al. : Diagnostic criteria for Werner syndrome based on Japanese nationwide epidemiological survey. Geriatr Gerontol Int. 2013;13(2):475–81. 10.1111/j.1447-0594.2012.00913.x - DOI - PubMed
    1. Yamaga M, Takemoto M, Shoji M, et al. : Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY). 2017;9(7):1738–44. 10.18632/aging.101265 - DOI - PMC - PubMed

    2. F1000 Recommendation