Structural insights into Cdc45 function: was there a nuclease at the heart of the ancestral replisome?

•The structure of human Cdc45 provides insight into its function in DNA replication as co-activator of the MCM helicase.•Structural analysis of human Cdc45 and bacterial RecJ illustrates the structural elements of their shared nuclease fold.•The structure of the archaeal GAN nuclease shows that it is an orthologue of eukaryotic Cdc45.•The Cdc45 subunit of the ancestral predecessor of archaeal and eukaryotic CMG helicases was a single-stranded DNA nuclease.

The role of Cdc45 in genomic duplication has remained unclear since its initial identification as an essential replication factor. Recent structural studies of Cdc45 and the evolutionarily-related archaeal GAN and bacterial RecJ nucleases have provided fresh insight into its function as co-activator of the MCM helicase. The CMG helicase of the last archaeal/eukaryotic ancestor might have harboured a single-stranded DNA nuclease activity, conserved in some modern archaea.

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