This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Every time a cell divides, it must accurately copy its entire genetic instruction manual. Before this process can begin, cells load their DNA-copying motor—a complex of six subunits known as the MCM2-7 helicase—onto DNA.
However, this motor is deliberately kept inactive to prevent replication from starting at the wrong time. Despite decades of research, scientists have not fully understood how cells switch this machinery on. Now, a team from the MRC Laboratory of Medical Sciences and Imperial College London, led by first authors Dr.
Almutasem Saleh and senior author Professor Christian Speck, has revealed the underlying structural changes that allow DNA replication to get underway. The study, published in Nature Communications, identifies how a specialized protein pair, Sld3 and Sld7, recognize that the MCM2-7 helicase is "switched on," allowing them to recruit a key component, Cdc45, needed to activate it and allow replication to proceed to its next steps. To make this discovery, the team first had to work out how the helicase itself is prepared for activation.
Previous research from other groups has shown that a flexible section of the Mcm4 subunit of the MCM2-7 helicase acts like a molecular "safety catch" by physically covering key surfaces on Mcm4 to keep the helicase switched off until the correct moment. Speck's team showed for the first time that it also covers surfaces on its neighboring subunit, Mcm6. A chemical tag added by an enzyme called DDK (via a process called phosphorylation) releases this safety catch, exposing the surfaces needed for the next steps of replication to begin.
This explains, at a structural level, how phosphorylation converts an inactive helicase into one that is ready for activation. The key discovery of this research was that a protein called Sld3 acts as a molecular sensor, helped into position by its partner, Sld7. Once the safety catch has been removed, Sld3 recognizes the newly exposed regions on Mcm4 and Mcm6 and binds to them.
In effect, it reads whether the machinery has been switched on and only proceeds when activation has occurred correctly. This provides an elegant explanation for how cells ensure DNA replication begins in the right place and at the right time. Perhaps the most surprising discovery was how Sld3 delivers an essential component known as Cdc45, which later becomes part of the active CMG helicase—the machine that ultimately unwinds the DNA double helix.
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