MSc by Research: The USP37 deubiquitylase: guardian of genome stability and a new target for anti-cancer therapy

The process of chromosome replication is defective in many cancer cells, which therefore have an increased dependency on pathways that allow cells to survive ‘DNA replication stress’.  Drugs inhibiting such pathways have great potential in the clinic – the best example is the ATR kinase that activates the ‘DNA damage checkpoint pathway’, which is essential for the survival of cells experiencing DNA replication stress.  ATR inhibitors are currently in Phase II trials as anti-cancer agents, but cancer cells can develop resistance to such inhibitors, making it important to identify additional pathways to inhibit, with a different mechanistic basis to ATR and the DNA damage checkpoint. 

Genome-wide CRISPR knockout screens indicate that mutation of the USP37 deubiquitylase makes cells just as sensitive to DNA replication stress as inhibition of ATR.  At present, it is unclear how USP37 protects cells from DNA replication stress, or what are the relevant targets of USP37 when chromosome replication is defective.  In our ongoing work, we have found that USP37 counteracts the action of two ubiquitin ligases that act at DNA replication forks.  These are CUL2LRR1 and TRAIP, which jointly control the ubiquitylation and disassembly of the chromosome replication machinery in mammalian cells.  Until now, however, it is unclear which targets of CUL2LRR1 or TRAIP might be protected from ubiquitylation by USP37 during DNA replication stress. 

After purifying USP37 from mammalian cells, we found by mass spectrometry that it interacts with two large protein complexes.  One is the replisome (the chromosome replication machinery) and the other is the cohesin complex that holds sister chromatids together before mitosis.  This suggests that USP37 might protect cells from DNA replication stress by preventing premature ubiquitylation of the replisome, or by counteracting cohesin ubiquitylation to preserve genome integrity.  The role of cohesin ubiquitylation has not previously been determined and so is a very interesting question for exploration. 

In this project, we will explore the molecular basis and functional implications of cohesin ubiquitylation in mammalian cells.  Using a combination of cutting-edge genetics, biochemistry and cell biology, we will try to identify which enzymes carry out cohesin ubiquitylation (e.g. CUL2LRR1, TRAIP, or other ubiquitin ligases), determine how USP37 counteracts cohesin ubiquitylation, and explore the functional implications.  This will involve a multi-disciplinary approach using techniques as CRISPR-mediated genome editing, protein purification, DNA cloning & sequencing, mass spectrometry, advanced imaging, structural predictions via AlphaFold, and biochemical validation of predicted interactions.  Cells lacking USP37 are highly sensitive to ATR inhibitors, and a deeper functional characterisation of USP37 will help to reveal its potential as a target for new anti-cancer therapies. 

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Life Sciences MSc by Research MSc by Research (Postgraduate) : Study : University of Dundee

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