title: The p53/p21(WAF/CIP) pathway mediates oxidative stress and senescence in dyskeratosis congenita cells with telomerase insufficiency.
abstract: Telomere attrition is a natural process that occurs due to inadequate telomere maintenance. Once at a critically short threshold, telomeres signal growth arrest, leading to senescence. Telomeres can be elongated by the enzyme telomerase, which adds de novo telomere repeats to the ends of chromosomes. Mutations in genes for telomere binding proteins or components of telomerase give rise to the premature aging disorder dyskeratosis congenita (DC), which is characterized by extremely short telomeres and an aging phenotype. The current study demonstrates that DC cells signal a DNA damage response through p53 and its downstream mediator, p21(WAF/CIP), which is accompanied by an elevation in steady-state levels of superoxide and percent glutathione disulfide, both indicators of oxidative stress. Poor proliferation of DC cells can be partially overcome by reducing O(2) tension from 21% to 4%. Further, restoring telomerase activity or inhibiting p53 or p21(WAF/CIP) significantly mitigated growth inhibition as well as caused a significant decrease in steady-state levels of superoxide. Our results support a model in which telomerase insufficiency in DC leads to p21(WAF/CIP) signaling, via p53, to cause increased steady-state levels of superoxide, metabolic oxidative stress, and senescence.
authors.affiliation: Interdisciplinary Program in Genetics, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Erik R
authors.initials: ER
authors.lastname: Westin
authors.forename: Nukhet
authors.initials: N
authors.lastname: Aykin-Burns
authors.forename: Erin M
authors.initials: EM
authors.lastname: Buckingham
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Spitz
authors.forename: Frederick D
authors.initials: FD
authors.lastname: Goldman
authors.forename: Aloysius J
authors.initials: AJ
authors.lastname: Klingelhutz
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics; D019871:Dyskeratosis Congenita / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D019098:Telomerase; D005978:Glutathione; D019803:Glutathione Disulfide