Werner syndrome: Molecular insights into the relationships between defective DNA metabolism, genomic instability, cancer and aging

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27 Scopus citations

Abstract

Werner syndrome is a segmental progeroid disease characterized by increased cancer and acceleration of specific age-related phenotypes, due to loss of a protein known as WRN. Extensive research over the last decade has revealed much about WRN biochemistry and the etiology of Werner syndrome. WRN possesses multiple DNA-dependent enzymatic activities (ATPase, helicase, exonuclease, and strand annealing) and interacts with factors having established roles in DNA metabolic pathways. Although the exact functions of WRN remain unclear, accumulating evidence points to roles in proper resolution of replication blockage and in telomere maintenance. If WRN function is lost (as exemplified in cells from Werner patients), problems with replication and DNA damage processing arise, probably resulting in an increased number or persistence of strand breaks. In turn, these events lead to chromosomal and telomeric abnormalities or activate checkpoints that bring about early senescence or increased apoptosis. Thus, elevated cancer incidence associated with Werner syndrome is due to increased chromosomal changes, while the accelerated aging characteristics probably stem from telomere dysfunction leading to accumulation of non-functional senescent cells or excessive apoptotic cell death over time. More research is needed to determine whether these specific DNA-dependent mechanisms contribute to development of aging characteristics in normal individuals.

Original languageEnglish
Pages (from-to)2657-2671
Number of pages15
JournalFrontiers in Bioscience
Volume11
Issue numberSUPPL. 2
DOIs
StatePublished - 2006

Keywords

  • Aging
  • Apoptosis
  • Cancer
  • Genomic Instability
  • RecQ helicases
  • Review
  • Senescence
  • Telomeres
  • Werner syndrome

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

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