%0 Journal Article %A Jingyu Chen %A Ian T Lobb %A Pierre Morin %A Sonia M Novo %A James Simpson %A Kathrin Kennerknecht %A Fiona Oakley %A Lesley A. Stark %T Activation of NF-κB by a novel, CDK4-regulated, nucleolar stress response pathway %D 2017 %R 10.1101/100255 %J bioRxiv %P 100255 %X The nucleolus is a multifunctional organelle that plays a critical role in maintaining cellular homeostasis under stress. However, how nucleoli sense stress and coordinate specific phenotypic outcomes, remains poorly understood. Here, we identify a novel nucleolar stress response pathway that culminates in activation of NF-κB. Using multiple approaches, we show that specific disruption of the PolI complex stimulates NF-κB signalling. Unlike the paradigm of nucleolar stress, this stimulation is not caused by inhibition of rRNA transcription. We identify a novel mechanism by which specific stresses disrupt nucleoli involving CDK4 inhibition and consequently, UBF-p14ARF-dependent degradation of the PolI complex component, TIF-IA. We show this atypical nucleolar stress response is associated with a distinctive nucleolar architecture. Furthermore, we show it lies upstream of NF-κB signalling. Finally, we explore the relevance of this pathway in response to aspirin in human clinical samples and demonstrate a correlation between TIF-IA degradation and NF-κB pathway activation. Together, these data provide a conceptual advance in understanding of nucleolar stress response with therapeutic implications. %U https://www.biorxiv.org/content/biorxiv/early/2017/01/13/100255.full.pdf