Apart from its role in ribosome biogenesis, the nucleolus acts as a cellular sentinel which monitors the cell for changes, and coordinates a response if issues are detected. This 'nucleolar surveillance response’ can rapidly mediate cell cycle arrest, apoptosis, or senescence depending on the cell type and severity of the insult to the cell. Often, this response requires the accumulation of the tumour suppressor protein p53, which occurs due to the sequestration of MDM2 by free ribosomal proteins. Work performed by our group has demonstrated that this process is responsible for the apoptotic cell death of cancer cells treated with CX-5461, a Pol I transcription inhibitor. Intriguingly, evidence also exists for the aberrant activation of this response in ribosomopathies (such as Diamond-Blackfan Anaemia, DBA), for which treatment options are limited. Yet the precise molecular mechanism underlying the p53-dependent mechanism remains elusive, and much detail is lacking.
To address this, we have taken a novel approach of performing genome-wide high throughput loss-of-function (RNAi) screens, to unbiasedly ascertain the critical genes and pathways implicated in the p53-mediated nucleolar stress response, as well as identify genes which modify the p53 response due to ribosomal protein insufficiency (as observed in DBA). We have uncovered a suite of novel genes and biological processes involved in this process, which we are currently validating using in vitro and in vivo models. Apart from obtaining a better understanding of this process, these studies will enable the development of (i) treatments for ribosomopathies and (ii) second-generation drugs to activate this response for use as potential cancer therapeutics.