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Multiple Involvement of Oxidative Stress in Werner Syndrome Phenotype

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Abstract

Werner syndrome is a genetic disease characterized by early ageing, excess cancer risk, high incidence of type II diabetes mellitus, early atherosclerosis, ocular cataracts, and osteoporosis. The protein encoded by the defective gene, WRN (WRNp) associates with three activities, that is, a RecQ DNA helicase, 3′-5′-exonuclease and ATPase activities. By highlighting the DNA helicase activity, a widespread consensus in WS-associated defect(s) has been established, pointing toward a deficiency in maintaining DNA integrity. However, a possible involvement of redox pathways in WS may be suggested by several lines of evidence that include: (i) the multiple functions and interactions of WRNp with oxidative stress-related activities and factors; (ii) the pleiotropic WS clinical phenotype encompassing a number of oxidative stress-related pathologies; (iii) redox-related toxicity mechanisms of several xenobiotics exerting excess toxicity in WS cells; (iv) recent in vivo and in vitro findings of redox abnormalities in WS patients and in WS cells. The working hypothesis is raised that a deficiency in WRNp, and the pleiotropic clinical phenotype in WS patients may provide the basis to envision an underlying in vivo prooxidant state, which causes oxidative damage to biomolecules, with multiple oxidative stress-related alterations, resulting in multi-faceted clinical consequences.

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Abbreviations

CPT:

camptothecin

GSH:

glutathione

MMC:

mitomycin C

MOP:

8-methoxypsoralen

NQO:

4-nitroquinoline-N-oxide

PARP-1:

poly(ADP-ribose) polymerase-1

PUVA:

8-methoxypsoralen and UV rays A

ROS:

reactive oxygen species

TNF-α:

tumour necrosis factor-α

top1:

topoisomerase I

WRN :

WS gene

WRNp:

WRN-encoded protein

WS:

Werner syndrome

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Authors and Affiliations

  1. Italian National Cancer Institute, “G. Pascale” Foundation, I-80131, Naples, Italy

    Giovanni Pagano

  2. Department of Genetics, “Elena d’Aosta” Hospital, I-80136, Naples, Italy

    Adriana Zatterale

  3. Italian National Cancer Institute, IST, I-16132, Genoa, Italy

    Paolo Degan

  4. Department of Organic Chemistry & Biochemistry, “Federico II” Naples University, I-80126, Naples, Italy

    Marco d’Ischia

  5. Division of Life Sciences, King’s College, SE1 9NN, London, UK

    Frank J. Kelly

  6. Department of Physiology, University of Valencia, E-46010, Valencia, Spain

    Federico V. Pallardó

  7. Frontier Science Innovation Center, The Industry-Academia-Government Collaboration Organization, Osaka Prefecture University, 599–8570, Osaka, Japan

    Seiji Kodama

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  1. Giovanni Pagano
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  2. Adriana Zatterale
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  3. Paolo Degan
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  4. Marco d’Ischia
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Correspondence to Giovanni Pagano.

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Pagano, G., Zatterale, A., Degan, P. et al. Multiple Involvement of Oxidative Stress in Werner Syndrome Phenotype. Biogerontology 6, 233–243 (2005). https://doi.org/10.1007/s10522-005-2624-1

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