Control of DNA Replication by Protein Dephosphorylation: the Role of Protein Phosphatase 1 and its Regulatory Interactors

DNA replication is central to life, with defects in this process a major cause of disease. Decades of study have revealed how phosphorylation of the replication machinery drives replication initiation. Dephosphorylation by protein phosphatases is also essential for DNA replication, but we do not understand why. Phosphatases are implicated in controlling the replication temporal programme, cell recovery from replication interruption, and replication protein recycling. However even for these established functions, we lack knowledge of the substrates dephosphorylated and their effects. These gaps in understanding limit opportunities for therapeutic intervention.

I aim for an integrated understanding of how Protein Phosphatase 1 (PP1) controls DNA replication. PP1 is targeted to substrates by a series of regulatory interactors, including RIF1 and NIPP1, which control the replication programme and recovery from DNA damage. My aim is to identify the molecular and structural basis of these controls, and to discover the precise mechanisms through which PP1 regulates normal and interrupted DNA replication. I will also test if other PP1 regulatory interactors control replication. Investigating DNA replication control from this new angle, my research programme will establish how PP1 integrates DNA replication with other cellular events, suggesting avenues for treatment of diseases caused by genome instability.