DNA replication is one of the most fundamental biological processes. The initiation of chromosome replication is highly regulated in eukaryotic cells, to ensure that a single copy of each chromosome is produced in every cell cycle. Initiation is frequently mis-regulated in human cancer and represents an interesting target for new anti-cancer therapeutics. The current model for replication initiation is based on the research of budding yeast, which shows that assembly of the CDC45-MCM-GINS (CMG) helicase is the key regulated step during eukaryotic DNA replication initiation. Until now, it was unclear whether metazoa requires additional factors not present in yeast.

Recently, Prof. Hong Ye's group at the School of Life Sciences of Shandong University and Collaborators from the MRC protein phosphorylation and ubiquitylation unit and MRC Laboratory of Molecular Biology in the UK published a research article in Science, entitled " DNSN-1 recruits GINS for CMG helicase assembly during DNA replication initiation in Caenorhabditis elegans", which identified a new regulator named DNSN-1 in CMG assembly.

This study used the model organism C. elegans to investigate the regulators of CMG helicase and found that DNSN-1 is essential for DNA replication. The human ortholog of DNSN-1, known as DONSON, was previously identified as a genome stability factor that is mutated in microcephalic primordial dwarfism called Meier-Gorlin syndrome. DNSN-1 is required to recruit the GINS complex to chromatin, and a cryo-electron microscopy structure indicates that DNSN-1 positions GINS on the MCM-2-7 helicase motor, by direct binding of DNSN-1 to GINS and MCM-3, using interfaces that are important for initiation and essential for viability. These findings represent a breakthrough in our understanding of DNA replication initiation, suggesting that initiation defects underlie the human disease syndrome resulting from DONSON mutations.

This work was supported by the National Natural Science Foundation of China and the Programs of Shandong University Qilu Young Scholars.

Link to this paper:DOI: 10.1126/science.adi4932