Defining the role of the E3 ubiquitin ligase UBR5 in cancer

Abstract

Despite recent advances, breast cancer remains a major burden on the healthcare system in Australia and abroad. Of particular concern are cancer subtypes that currently lack targetted therapeutics. As such, the continued development of targetted therapeutics remains a high priority. The ubiquitin system offers a fresh avenue for the development of targetted therapeutics. Ubiquitin tagging (ubiquitylation) is a very common posttranslational modification of proteins that signals degradation, changes in protein interactions and other outcomes. UBR5 is a protein originally identified as a tumour suppressor in Drosophila that catalyses attachment of ubiquitin to substrate proteins. UBR5 is amplified in a significant proportion of cancers, particularly in breast and ovarian. Intriguingly, UBR5 amplification correlates with a significantly poorer survival for breast cancer patients. Although UBR5 has well characterised roles in development and orchestrating a cellular response to DNA damage, it is unknown how UBR5 amplification may contribute to a poorer patient outcome. This study aims to comprehensively characterise the role of UBR5 in breast cancer biology using cellular and animal models. UBR5 does not fit into a classical binary definition of either oncogene or tumour suppressor, as initial studies manipulating UBR5 expression did not reveal a significant role for UBR5 in basic processes such as increased proliferation or invasion/metastasis. This study identified a novel role for UBR5 primary cilia formation (ciliogenesis). Primary cilia are antennae like structures important for cellular signalling in most cell types. Functional studies showed UBR5 to act upstream of cilia formation on granular structures known as centriolar satellites. Further work described a mechanism whereby UBR5 ubiquitylates the cilia protein CSPP1 via a non-degrading lysine 63-linked ubiquitin chain, altering sub-cellular localisation. This work represents a major step forward in understanding the biology of primary cilia, with implications for not only cancer, but also a rare group of disorders known as ciliopathies that are characterised by cilia dysfunction. To the best of our knowledge aberrations in UBR5 has not been studied in this context, and future experiments should examine a genetic link between UBR5 and cilia dysfunction in cohorts of ciliopathies.