The nucleoli are the site of RNA polymerase I (Pol I) transcription of ribosomal RNA (rRNA) genes and ribosome assembly. The first-in-class inhibitor of Pol I transcription, CX-5461, has shown promising anti-tumour activity in various preclinical cancer models and in Phase I clinical trials in blood and solid cancers. Our work has shown that CX-5461 activates a unique form of stress, termed nucleolar stress, leading to inhibition of cell proliferation with low levels of global DNA damage. CX-5461 has a unique sensitivity profile compared to chemotherapeutics. Thus, we propose that activating nucleolar stress represents a promising new cancer therapy paradigm.
To characterize nucleolar stress pathways, we have performed a whole-genome synthetic lethal RNA interference screen and identified that CX-5461 is synthetic lethal with various DNA repair pathways, highlighting the strong links between nucleolar stress and global DNA replication stress. We have recently completed an innovative arrayed CRISPR-Cas9 screen to identify genes whose deletion induces changes in nucleolar morphology as an indicator of nucleolar stress. We have identified factors involved in ribosome biogenesis, DNA replication, cell cycle and RNA metabolism as mediators of nucleolar stress.
Altogether, our work defines nucleolar stress pathways and highlights harnessing nucleolar stress as a novel cancer therapy approach. This project aims to validate targets identified in our screens as mediators of nucleolar stress and novel cancer therapeutic targets
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