RT Journal Article
SR Electronic
T1 Inhibition of the 60S ribosome biogenesis GTPase LSG1 causes endoplasmic reticular disruption and cellular senescence
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 463851
DO 10.1101/463851
A1 Asimina Pantazi
A1 Andrea Quintanilla
A1 Priya Hari
A1 Nuria Tarrats
A1 Eleftheria Parasyraki
A1 Flora Lucy Dix
A1 Jaiyogesh Patel
A1 Tamir Chandra
A1 Juan Carlos Acosta
A1 Andrew John Finch
YR 2018
UL http://biorxiv.org/content/early/2018/11/08/463851.abstract
AB Cellular senescence is triggered by diverse stimuli and is characterised by long-term growth arrest and secretion of cytokines and chemokines (termed the SASP - senescence-associated secretory phenotype). Senescence can be organismally beneficial as it can prevent the propagation of damaged or mutated clones and stimulate their clearance by immune cells. However, it has recently become clear that senescence also contributes to the pathophysiology of aging through the accumulation of damaged cells within tissues. Here we describe that inhibition of the reaction catalysed by LSG1, a GTPase involved in the biogenesis of the 60S ribosomal subunit, leads to a robust induction of cellular senescence. Perhaps surprisingly, this was not due to ribosome depletion or translational insufficiency, but rather through perturbation of endoplasmic reticulum (ER) homeostasis and a dramatic upregulation of the cholesterol biosynthesis pathway. This cholesterol/ER signature is shared with several other forms of senescence and contributes to the cell cycle arrest in oncogene-induced senescence (OIS). Furthermore, targetting of LSG1 resulted in amplification of the cholesterol/ER signature and restoration of a robust cellular senescence response in transformed cells, suggesting potential therapeutic uses of LSG1 inhibition.