Werner syndrome: molecular insights into the relationships between defective DNA metabolism, genomic instability, cancer and aging.
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.
Orren
David K
DK
Graduate Center for Toxicology, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0305, USA. dkorre2@uky.edu
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000375:Aging / Q000235:genetics*; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D004265:DNA Helicases / Q000378:metabolism; D004260:DNA Repair; D004261:DNA Replication; D042822:Genomic Instability; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D010641:Phenotype; D016615:Telomere / Q000378:metabolism; D014898:Werner Syndrome / Q000235:genetics* / Q000503:physiopathology
D004247:DNA; D000251:Adenosine Triphosphatases; D004265:DNA Helicases