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Supervisors:

Vincenzo D'Angiolella

Ross Chapman (external)

Project Details:

Normal cells coordinate the production of deoxyribonucleotides (dNTPs) with DNA replication. On the contrary, cancer cells proliferate uncontrollably and need to balance faster DNA replication with a high demand for dNTPs. Sometime the demand for dNTPs is not sustainable and cancer cell experiences DNA replication stress. 

A central enzyme that controls the production of dNTPs in mammalian cells is the Ribonucleotide Reductase (RNR), which converts NTPs to their corresponding dNTPs. The regulation of RNR is crucial to guarantee enough dNTPs in each DNA replication cycle. Our group revealed how regulation of RNR balances dNTP production with cell cycle progression to prevent genome instability (1-4). More recently, the group has generated a system to study the consequences of limiting nucleotides for genome integrity.

The current project seeks to determine how limiting dNTPs alter genome stability and identify key therapeutic vulnerabilities induced by limiting dNTPs. The study may reveal novel approaches to increase the efficacy of current cancer treatments and help to select patients that most likely will benefit of chemotherapy and immunotherapy. Training will be provided in cellular and molecular biology techniques including CRISPR screens and super-resolution microscopy.