Mechanistic Investigation Of Long Non-coding RNA GUARDIN In Cellular Senescence

Cellular senescence is an irreversible state of cellular dormancy driven by various mechanisms such as replicative exhaustion resulting from telomere shortening or uncapping,oncogene activation,and genotoxic,nutrient and oxidative stress.These mechanisms commonly cumulate in the DNA damage response(DDR)leading to activation of the tumor suppressor p53 and the expression of cyclin-dependent kinase(CDK)inhibitors such as p21 and p16 that execute the senescent response.Although cellular senescence was initially regarded as a passive cell-autonomous anti-proliferation program echoing normal cellular aging,it is increasingly appreciated that senescence plays an important role in many other physiological and pathological processes including tumor suppression,neurodegeneration and tissue remodeling.Moreover,the senescence-associated secretory phenotype(SASP)resulting from changes in the secretome of senescent cells contributes to regulating inflammation,tissue microenvironment and age-related disorders.An increasing number of noncoding RNAs have been found to be involved in regulation of cellular senescence.For example,the long noncoding RNA MIR31HG regulates the expression of p16 to modulate oncogene-induced senescence,whereas HOTAIR activates cellular senescence through p53-p21 signaling of the DDR.Moreover,the lncRNA OVAAL blocks cellular senescence through regulating the expression of the CDK inhibitor p27.We have also found that the lncRNA GUARDIN plays an essential role in maintaining genomic stability.Silencing of GUARDIN was shown to induce cellular senescence although the mechanism responsible remains undefined.As an important regulatory mechanism of cellular senescence that integrates a variety of extracellular and intracellular signals,the mechanistic target of rapamycin(mTOR;as known as mammalian target of rapamycin)plays an important role in regulating longevity.Inhibition of mTOR signaling by genetic or pharmacological approaches extends lifespan of various model organisms and mice with different genetic backgrounds.Indeed,treatment with the mTOR inhibitor rapamycin or its analogs(rapalogs)reduces cellular senescence.Nevertheless,the molecular mechanisms involved in rapamycin-mediated inhibition of senescence are not well understood.In this report,we demonstrate that GUARDIN serves to facilitate assembly of the complex between LRP130/PGC1? that acts as repressor complex at the FOXO4 promoter.Silencing of GUARDIN disrupts this complex leading to FOXO4-dependent upregulation of p21,thereby driving cell entry into cellular senescence.On the other hand,GUARDIN expression is upregulated by rapamycin treatment and this result from modulation of FOS-Like Antigen 2(FOSL2)levels.FOSL2 normally transcriptionally represses GUARDIN but downregulation of FOSL2 by rapamycin releases this inhibition to promote GUARDIN expression.Thus,GUARDIN inhibits p21-dependent senescence induction through a signaling axis involving LRP130-PGC1?-FOXO4 moreover plays a functional role in the antagonistic actions of rapamycin on cellular senescence.