Study reveals key steps in switching on DNA replication
image:
Structural view of the MCM2-7 helicase with Sld3, Sld7 and Cdc45 bound at the site where Cdc45 is delivered. Structure derived from cryogenic electron microscopy data. Noguchi et al., 2026.
view moreCredit: DNA Replication Group, MRC Laboratory of Medical Sciences
Researchers at the MRC Laboratory of Medical Sciences (LMS), Imperial College London and their collaborators have uncovered a crucial mechanism that cells use to control when to start DNA copying. This helps scientists understand one of the most fundamental processes in biology – how cells accurately duplicate their genomes.
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 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 Yasunori Noguchi and 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 specialised protein pair, Sld3 and Sld7, recognise 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 the next steps.
Understanding the molecular safety catch
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 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. Christian’s team showed for that first time that it also covers surfaces on its neighbouring 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.
How cells know the machinery is ready
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 recognises 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.
Delivering a crucial component
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.
The researchers found that Sld3 acts like a molecular adaptor. It first anchors itself to the Mcm2 part of the helicase, senses that activation has occurred and then repositions across the helicase to deliver Cdc45 to a different site, at the interface between Mcm2 and Mcm5.
When the team altered the amino acids at this newly identified Sld3–Cdc45 contact point, the machinery could still bind the helicase but could no longer recruit Cdc45 – demonstrating that this connection is essential for activation.
Capturing a previously hidden stage
The study also captured an intermediate stage between an inactive helicase and the fully active CMG motor. Rather than attaching immediately in its final position, Cdc45 first enters a partially connected state, with a further protein complex called GINS proposed to arrive afterwards to stabilise it and complete the active machine.
These structural snapshots provide an unprecedented view of the events that occur as cells prepare to copy their genomes.
Why does this matter?
Although the work was carried out using yeast proteins, the core machinery involved in DNA replication is highly conserved across species. The researchers found structural evidence suggesting that Treslin, the human counterpart of Sld3, may recruit Cdc45 by a similar principle, though this still needs to be tested experimentally.
The research does not provide an immediate treatment or medical application. Instead, its significance lies in helping scientists understand one of the most fundamental processes in biology: how cells accurately duplicate their genomes.
Genome duplication must be tightly controlled. Errors in the process can threaten genome stability and are linked to diseases in which DNA replication becomes disrupted. By revealing how cells activate the machinery that starts replication, the study provides an important foundation for future research in this area.
"Our cells must copy billions of DNA letters accurately every time they divide, so the machinery that starts this process has to be controlled with exceptional precision. We have now been able to see how a phosphorylation signal releases a molecular safety catch, how Sld3 recognises that signal and how it then delivers Cdc45 to assemble the DNA-unwinding motor. Understanding this sequence gives us a much clearer picture of the intricate regulation that protects the stability of cellular genomes," says Christian.
This study was funded by the Biotechnology and Biological Sciences Research Council and the Wellcome Trust.
Journal
Nature Communications
Article Title
Structural insights into Sld3-Sld7-dependent Cdc45 loading during replication initiation
Article Publication Date
14-Aug-2026
How plants selectively silence jumping genes while protecting essential genes
Researchers reveal how histone variants direct DNA methylation to jumping genes while preventing accidental gene silencing
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Researchers reveal that histone variant H2A.W promotes DNA methylation at transposons, facilitating their inactivation, whereas H2A.Z suppresses DNA methylation and is enriched in gene regions.
view moreCredit: Institute of Science Tokyo (Science Tokyo), Japan
Histone variants help establish DNA methylation at transposons (jumping genes) while preventing this epigenetic modification from spreading to essential genes in plants, reveals a study from Institute of Science Tokyo. By revealing how these chromosome-associated proteins guide the formation of precise epigenomic patterns, the findings provide new insights into the selective silencing of transposons, laying the groundwork for future epigenome-editing technologies for crop improvement and disease research.
Plants and animals have multiple transposons or “jumping genes” in their genome. These are mobile DNA elements that are capable of moving to new locations within the genome. Although transposons have contributed to genome evolution, their movement can disrupt genes and compromise genome stability, leading to diseases such as cancer. To prevent this, organisms often rely on epigenetic mechanisms (cellular processes such as DNA methylation that control gene expression without changing the underlying DNA sequence) to keep these transposons inactive.
But as both transposons and essential genes coexist within the same genome, an important question arises: How do cells selectively target transposons without accidentally silencing essential genes?
To address this question, a research team led by Associate Professor Taiko Kim To and Dr. Shoda Oda from the Department of Life Science and Technology, School of Life Science and Technology, Institute of Science Tokyo (Science Tokyo), Japan, along with colleagues and researchers from The University of Tokyo, Japan; Chiba University, Japan; Kyoto Sangyo University, Japan; and Vienna Biocenter, Austria, investigated the role of histone variants (slightly different forms of the histone proteins around which DNA is wrapped) in establishing DNA methylation. Their findings were published online in the journal Nature Communications on June 30, 2026.
Using genetically engineered mutants of the model plant Arabidopsis thaliana lacking specific histone variants, the researchers restored DNA methylation through selective regulation and tracked how epigenetic patterns were re-established across the genome under different histone variant compositions. The experiments revealed that the histone variant H2A.W promotes DNA methylation at transposons, facilitating their inactivation. In contrast, H2A.Z suppresses DNA methylation and is enriched in gene regions, where it protects important genes from being mistakenly silenced.
"We observed that these opposing functions were particularly evident in gene-rich regions of the genome, where accurate epigenetic regulation is especially critical," explains To.
The findings demonstrate that histone variants act as molecular guides that determine where DNA methylation should be established, by enabling plants to selectively inactivate the transposons while preserving normal gene activity. Additionally, the study also reveals that the genomic environment influences how epigenetic patterns are restored. In chromosome arms that are rich in essential genes, the transposons are dispersed among the genes. Here, the opposing actions of H2A.W and H2A.Z are crucial for accurately re-establishing the DNA methylation.
In contrast to this, heterochromatin (the tightly packed form of DNA that keeps transposons inactive) was recovered much more robustly in transposon-rich pericentromeric regions, suggesting that these regions possess an intrinsic ability to re-establish their silenced state. These findings show that plants use complementary strategies to maintain genome stability by combining local molecular guidance by histone variants with autonomous recovery of heterochromatin in transposon-dense regions.
Overall, the study uncovers a molecular framework that enables plant cells to distinguish transposons from genes, ensuring precise epigenetic regulation across the genome. Since the functions of histone variants are often conserved across evolution, the researchers suggest that the mechanism uncovered in plants may also help explain how epigenetic regulation is achieved in other organisms as well. The findings, therefore, provide a broader framework for understanding genome regulation beyond the plant kingdom.
“Although our work was carried out in plants, histone variants are conserved across many organisms,” adds To. "This knowledge could inspire future epigenome-editing technologies for agriculture and medicine."
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About Institute of Science Tokyo (Science Tokyo)
Institute of Science Tokyo (Science Tokyo) was established on October 1, 2024, following the merger between Tokyo Medical and Dental University (TMDU) and Tokyo Institute of Technology (Tokyo Tech), with the mission of “Advancing science and human wellbeing to create value for and with society.”
Journal
Nature Communications
Method of Research
Experimental study
Subject of Research
Not applicable
Article Title
Antagonistic histone H2A variants and autonomous heterochromatin formation shape epigenomic patterns in Arabidopsis
