MCM10 and SLD-2/RECQL4 jointly activate the CMG helicase during metazoan DNA replication initiation

Eukaryotic cells regulate the assembly and activation of the essential DNA helicase at the heart of the chromosome replication machinery, to ensure that the chromosomes are copied just once per cell cycle. The Mcm10 protein is essential for helicase activation in budding yeast, but an equivalent role for MCM10 orthologues in animal cells has not been explored. Moreover, complete deletion of the mcm-10 gene is viable in the nematode Caenorhabditis elegans, suggesting the involvement of additional factors. Here we show that MCM-10 and a second factor called SLD-2 are recruited to chromatin after helicase assembly in the C. elegans early embryo and are partially redundant for helicase activation. Moreover, deletion of the Mcm10 gene is viable in mouse embryonic stem cells, but causes synthetic lethality in the absence of RECQL4, which is the orthologue of SLD-2 in vertebrate species. Helicase activation is blocked in the combined absence of MCM10 and RECQL4, mirroring the situation in C. elegans. These findings indicate that metazoan helicase activation requires two conserved factors that are mutated in human disease.