ATM kinase enables the functional axis of YAP, PML and p53 to ameliorate loss of Werner protein-mediated oncogenic senescence.

[werner syndrome]

Werner syndrome (WS ) results from dysfunction of the WRN protein , and is associated with premature aging and early death . Here we report that loss of WRN function elicits accumulation of the Yes-associated protein (YAP protein ), a major effector of the Hippo tumor suppressor pathway , both experimentally and in WS -derived fibroblasts . YAP upregulation correlates with slower cell proliferation and accelerated senescence , which are partially mediated by the formation of a complex between YAP and the PML protein , whose activity promotes p 53 activation . The ATM kinase is necessary for YAP and PML accumulation in WRN -depleted cells . Notably , the depletion of either YAP or PML partially impairs the induction of senescence following WRN loss . Altogether , our findings reveal that loss of WRN activity triggers the activation of an ATM -YAP-PML -p 53 axis , thereby accelerating cellular senescence . The latter has features of SASP (senescence-associated secretory phenotype ), whose protumorigenic properties are potentiated by YAP , PML and p 53 depletion .

Diseases
Validation

Diseases presenting "early death" symptom

hirschsprung disease

junctional epidermolysis bullosa

krabbe disease

neonatal adrenoleukodystrophy

pyruvate dehydrogenase deficiency

werner syndrome

zellweger syndrome

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