Werner syndrome: Association of premature aging and cancer predisposition

Byungchan Ahn, Tinna Stevnsner, Vilhelm A. Bohr

    Publikation: Bidrag til bog/antologi/rapport/proceedingBidrag til bog/antologiForskningpeer review


    Introduction Werner syndrome (WS) is a rare autosomal recessive disorder in humans characterized by segmental premature aging. Somatic cells from WS individuals show low replicative capacity, hypersensitivity to DNA-damaging agents, increased genome instability, and altered telomere maintenance (1). The incidence of sarcomas is significantly higher in WS patients than in normal individuals (1). Genetic evidence indicates that WS is caused by loss of function mutations in the WRN gene, which encodes a protein that belongs to the RecQ family of DNA helicases. Polymorphisms in WRN have been demonstrated to be associated with breast cancer (2) and soft tissue sarcomas (3,4). The WRN gene has been cloned and the properties of WS cells and WRN protein have been studied extensively. Nevertheless, the pathophysiology of WS and the cellular and molecular mechanisms involved in WS pathogenesis remain poorly understood. Because WS is a progerioid disease, it is used as a model system to better understand the process of aging in humans. The exact biological role of WRN remains unknown. However, it has been proposed that it plays roles in the response to DNA damage. In particular, WRN may promote rescue of stalled replication forks and help resolve recombination intermediates in cells experiencing replicative stress. WRN also plays a role in telomere replication and alternative lengthening of telomeres. Thus, loss of function mutations in WRN could disrupt DNA replication and DNA-damage processing, resulting in accumulation of DNA double-strand breaks (DSBs) and recombination intermediates. These events could activate cell-cycle checkpoints resulting in senescence, apoptosis, or genetic instability leading to cellular transformation. These molecular endpoints could ultimately lead to features of premature aging and/or increased cancer susceptibility (Figure 35.1). This chapter discusses how WRN may contribute to genome stability and reduce cancer susceptibility.

    TitelMolecular Oncology : Causes of Cancer and Targets for Treatment
    RedaktørerEdward P. Gelmann, Charles L. Sawyers , Frank J. Rauscher, III
    Antal sider11
    ForlagCambridge University Press
    ISBN (Trykt)9780521876629
    ISBN (Elektronisk)9781139046947
    StatusUdgivet - 2015


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