Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells.

[werner syndrome]

The Werner syndrome protein (WRN ) is a nuclear protein required for cell growth and proliferation . Loss -of-function mutations in the Werner syndrome gene are associated with the premature onset of age-related diseases . How loss of WRN limits cell proliferation and induces replicative senescence is poorly understood . Here , we show that WRN depletion leads to a striking metabolic shift that coordinately weakens the pathways that generate reducing equivalents for detoxification of reactive oxygen species and increases mitochondrial respiration . In cancer cells , this metabolic shift counteracts the Warburg effect , a defining characteristic of many malignant cells , resulting in altered redox balance and accumulation of oxidative DNA damage that inhibits cell proliferation and induces a senescence-like phenotype . Consistent with these findings , supplementation with antioxidant rescues at least in part cell proliferation and decreases senescence in WRN -knockdown cancer cells . These results demonstrate that WRN plays a critical role in cancer cell proliferation by contributing to the Warburg effect and preventing metabolic stress .

Diseases
Validation

Diseases presenting "loss-of-function mutations" symptom

achondroplasia

alpha-thalassemia

aromatase deficiency

child syndrome

cowden syndrome

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erythropoietic protoporphyria

esophageal adenocarcinoma

familial hypocalciuric hypercalcemia

harlequin ichthyosis

hirschsprung disease

kallmann syndrome

kindler syndrome

lamellar ichthyosis

neonatal adrenoleukodystrophy

pendred syndrome

werner syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated