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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