Methodology for the identification of small molecule inhibitors of the Fanconi Anaemia ubiquitin E3 ligase complex
Michael F Sharp, Vince J Murphy, Sylvie Van Twest, Winnie Tan, Jennii Lui, Kaylene J Simpson, Andrew J Deans, Wayne Crismani
SCIENTIFIC REPORTS | NATURE RESEARCH | Published : 2020
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-u..View full abstract
Awarded by National Health and Medical Research Council (Career development fellowship)
Awarded by Education Investment Fund
Thank you to Rohan Bythell-Douglas for helpful comments on the manuscript. This work has been supported by funding from the National Health and Medical Research Council (Career development fellowship GNT1129757 to W.C., a project grant GNT1156343 awarded to W.C., A.J.D. and K.J.S.), Maddie Riewoldt's Vision (MRV Fellowship WC-MRV2016 to W.C. and Grant-In-Aid SVI-MRV2017G to W.C. and A.D.), the Victorian Cancer (Victorian Cancer Agency Fellowship to A.J.D.) and the Victorian government IOS program. W.T. was supported by an Australian Government Research Training Scheme postgraduate scholarship. The Victorian Centre for Functional Genomics (K.J.S.) is funded by the Australian Cancer Research Foundation (ACRF), the Australian Phenomics Network (APN) through funding from the Australian Government's National Collaborative Research Infrastructure Strategy (NCRIS) program, the Peter MacCallum Cancer Centre Foundation and the University of Melbourne Research Collaborative Infrastructure Program. We thank Compounds Australia Griffith University for their provision of specialized comrnment "Smart State Repound management and logistics services to the project. Griffith is a recipient of Queensland Govesearch Facilities Fund" funding and Australian Government funding provided under the "Super Science Initiative" and financed from the Education Investment Fund. The SUM149 and SUM149 B1.S* cells were a gift from Stephen Pettitt and Christopher Lord.