Beyond the Ribosome: The role of the nucleolus in development and cancer

The nucleolar stress response (NSR) is an essential and evolutionarily conserved mechanism by which cells, via the nucleolus, interpret changes to ribosome biogenesis, and converts these signals into decisions about cell fate. In the canonical NSR pathway, severe disruption to ribosome biogenesis leads to loss of nucleolar integrity and p53 protein accumulates due to the inhibitory binding of a ribonucleoprotein (RNP) complex containing 5S rRNA and the ribosomal proteins (RP), to the p53-targeting ubiquitin ligase MDM2. The resultant elevated p53 and thus p53-dependent transcription drives cell cycle arrest, apoptosis or senescence depending on cell type and insult severity. In addition to reacting to major insults on ribosome biogenesis, the NSR most likely operates continually under normal conditions, tightly linking the normal fluctuations in on-going ribosome synthesis with p53 levels.

Pathophysiological hyperactivation of NSR occurs in a collection of diseases called ribosomopathies due to genetic lesions in components of the ribosome biogenies pathway. In contrast we have shown that hyperactivation of the NSR, in response to small molecule inhibitors of ribosome biogenesis, can be exploited as a therapeutic strategy to selectively kill malignant cells. Despite the fundamental importance of the NSR for cell survival and cell fate decisions, the molecular process and components involved in the NSR are poorly understood and are subject to conflicting data. To address these shortcomings in knowledge we have used high-throughput unbiased functional genomic screening approaches to identify novel candidates and pathways that regulate the NSR. The finding of these screens and their application to new treatments for ribosomopathies and cancer will be presented. In addition, we will present evidence to support the hypothesis that the nucleolus functions as the central coordinator of all cellular stresses that activate p53.

Professor Ross Hannan PhD, FAHMS

Professor Hannan is an NHMRC Senior Principal Research Fellow, ANU Foundation Centenary Chair in Cancer Research, Head of the Department of Cancer Biology and Therapeutics at John Curtin School of Medical Research, ANU, Canberra, a group leader at the Peter MacCallum Cancer Centre, Melbourne and Executive Director of Research, ACT Health.

Professor Hannan’s research career spans over 20 years of internationally competitive research in Australia and the USA working on the genetic and epigenetic regulation of ribosomal gene transcription in cancer and nucleolar stress. Most recently he brought together multi-disciplinary teams of laboratory and clinician researchers and forged industry collaborations to devise ‘first in class’ cancer therapies targeting RNA Polymerase I that are now in clinical trials for a range of human cancers.

Professor Hannan’s achievements have been recognised by his election to the Fellowship of the Australian Academy of Health and Medical Sciences (2017). In 2017 he was appointed as a Director on the Board of the National Breast Cancer Foundation (NBCF) and Chair of the NBCF Scientific Advisory Board. As Executive Director of Research, ACT Health, Professor Hannan is focused on effective translation of research from fundamental science to the clinic; improvement of the health system through health service, clinical research, and clinical trials; growing and unlocking health opportunities with data science; and improving investment opportunities for ACT health innovations.

Seminar Host: Professor Rob Parton (r.parton@imb.uq.edu.au)