Journal
SCIENTIFIC REPORTS
Volume 10, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41598-020-64868-7
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Funding
- National Health and Medical Research Council (Career development fellowship) [GNT1129757, GNT1156343, WC-MRV2016, SVI-MRV2017G]
- Victorian Cancer (Victorian Cancer Agency Fellowship)
- Victorian government IOS program
- Australian Government Research Training Scheme postgraduate scholarship
- Australian Cancer Research Foundation (ACRF)
- Australian Phenomics Network (APN) through funding from the Australian Government's National Collaborative Research Infrastructure Strategy (NCRIS) program
- Peter MacCallum Cancer Centre Foundation
- University of Melbourne Research Collaborative Infrastructure Program
- Queensland Government Smart State Research Facilities Fund
- Australian Government
- Education Investment Fund [SUM149]
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DNA inter-strand crosslinks (ICLs) threaten genomic stability by creating a physical barrier to DNA replication and transcription. ICLs can be caused by endogenous reactive metabolites or from chemotherapeutics. ICL repair in humans depends heavily on the Fanconi Anaemia (FA) pathway. A key signalling step of the FA pathway is the mono-ubiquitination of Fanconi Anaemia Complementation Group D2 (FANCD2), which is achieved by the multi-subunit E3 ligase complex. FANCD2 mono-ubiquitination leads to the recruitment of DNA repair proteins to the site of the ICL. The loss of FANCD2 mono-ubiquitination is a common clinical feature of FA patient cells. Therefore, molecules that restore FANCD2 mono-ubiquitination could lead to a potential drug for the management of FA. On the other hand, in some cancers, FANCD2 mono-ubiquitination has been shown to be essential for cell survival. Therefore, inhibition of FANCD2 mono-ubiquitination represents a possible therapeutic strategy for cancer specific killing. We transferred an 11-protein FANCD2 mono-ubiquitination assay to a high-throughput format. We screened 9,067 compounds for both activation and inhibition of the E3 ligase complex. The use of orthogonal assays revealed that candidate compounds acted via non-specific mechanisms. However, our high-throughput biochemical assays demonstrate the feasibility of using sophisticated and robust biochemistry to screen for small molecules that modulate a key step in the FA pathway. The future identification of FA pathway modulators is anticipated to guide future medicinal chemistry projects with drug leads for human disease.
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