Protein Phosphatases and DNA Replication Initiation

Eukaryotic DNA replication is controlled by regulated cycles of protein phosphorylation. While the controls over these cycles of kinase activity have been the subject of intense investigation, controls over the removal of phosphorylation, carried out by protein phosphatases, are potentially of equal importance for regulating DNA replication but have in comparison been largely neglected. In this chapter we will first present a brief overview of the families of phosphatases occurring in eukaryotic cells, with emphasis on the PP1 and PP2A subtypes that have been implicated in direct control of replication origin initiation. We will then review our current knowledge of how these phosphatases interact with established control pathways to impact on replication initiation, outlining how PP1 activity is required to prevent premature origin initiation, and its potential involvement in dephosphorylating ORC to enable pre-replication complex formation. Possible pathways for the involvement of PP2A in promoting replication initiation will also be introduced, highlighting the gaps in our understanding and areas of ongoing investigation.