Scientists pinpoint where cells first begin copying DNA
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Dr Maximilan Reuter
Researchers at the Institute of Molecular Biology (IMB) in Mainz, Germany, and their collaborators at the MRC Laboratory of Medical Sciences (LMS) in the UK have uncovered one of the earliest steps in DNA replication: the moment a cell first opens its DNA to begin making a copy of its genome. The findings, published in Nature Communications, reveal where DNA first starts to "unzip" inside living cells and identify a molecular gate that helps prepare DNA for copying.
Every time a cell divides, it must faithfully copy its entire genetic instruction manual. Errors during this process can damage the genome, making DNA replication one of the most carefully controlled activities in biology.
Before DNA can be copied, cells must activate specialised molecular machines called helicases, which separate the two strands of the DNA double helix. A key part of this machinery is a protein complex of six subunits called MCM2-7, which forms a dimer of two rings around DNA at specific starting points called replication origins. When activated, these two rings split and form the core machinery of the two emerging replication forks – the structures where DNA copying takes place.
Despite decades of research, scientists have struggled to observe exactly how this process begins inside living cells. Important questions remained unanswered, including where DNA first opens, how one strand exits the helicase ring, and how the molecular changes needed to start replication are coordinated.
Now, research led by senior author Dr Maximilian Reuter at the Institute of Molecular Biology in Mainz, Germany, together with co-senior author Prof. Christian Speck and co-first author Dr Christopher Weekes at the MRC Laboratory of Medical Sciences and Imperial College London, has captured key steps of this transition in detail.
“DNA replication is fundamental to every cell division, yet we still did not fully understand how it begins inside living cells. We wanted to find out where the DNA first opens and how the helicase, the molecular zipper that separates the two DNA strands, is reorganised into its active form. By identifying these first steps, we can now explain more clearly how cells start copying their DNA in the right place and at the right time.”
- Dr Maximilan Reuter, Team Leader, IMB Mainz
Capturing where DNA first opens
Before DNA can be copied, helicases must first separate the two strands of the DNA double helix. Scientists often compare this process to unzipping a zip before reading or copying the information inside.
Using a combination of synthetic biology, genome-wide DNA mapping and protein analysis, the team was able to track this process inside living yeast cells. They found that DNA begins opening at a highly specific location near the interface where the two MCM2-7 rings meet.
The study also showed that this first opening event occurs in the same small region of DNA that is used to recruit the proteins responsible for starting replication, suggesting that multiple stages of DNA copying are coordinated within a compact area of the genome.
Revealing DNA’s molecular exit gate
The researchers also identified a specialised “gate” within the helicase complex used during the earliest stages of DNA replication. They found evidence that this opening acts as a molecular doorway through which one strand of DNA exits as the replication machinery becomes active.
When the team attached a molecular string to neighbouring subunits of each helicase, DNA began to open, but the replication machinery could not form properly functioning replication forks, as the strings would lead to their entanglement.
This revealed that the gate plays a critical role during activation of the replication machinery, helping cells transition from preparing for DNA replication to actively copying the genome.
Building a complete picture of replication initiation
As well as identifying where DNA first opens, the study linked several previously separate steps into a single framework. The researchers showed how DNA opening, helicase separation, strand release and the arrival and departure of replication proteins are coordinated as replication begins.
They also captured previously unseen intermediate states of the replication machinery, helping to explain how cells transform inactive protein complexes into fully operational DNA-copying machines.
Why does this matter?
This research is a fundamental advance in our understanding of how cells preserve and pass on genetic information. Accurate DNA replication is essential for genome stability, and mistakes during the process can leave DNA damaged or incompletely copied.
While the work does not have an immediate clinical application, many of the proteins involved are conserved from yeast to humans, meaning the principles uncovered in this study could help researchers better understand replication and genome maintenance across a wide range of organisms.
The study also highlights the value of investigating molecular processes inside living cells, revealing not just what biological machines look like, but how and where they operate across the genome.
“Starting DNA replication is not simply a matter of switching on a molecular motor. Two helicase rings must separate, open the DNA, release temporary assembly factors and move past one another in precisely the correct order. By mapping where DNA first opens in living cells and identifying the gate through which one strand exits, we can now explain this fundamental transition with much greater precision.”
- Prof. Christian Speck, Head of the DNA Replication Group, LMS
Further details
Read the full paper here: www.nature.com/articles/s41467-026-75695-1
Max Reuter is a Team Leader in the group of Helle Ulrich. Further information about Max’s research can be found at www.imb.de/research/ulrich/team-leader-reuter.
This study was funded by the Biotechnology and Biological Sciences Research Council, Cancer Research UK and Deutsche Forschungsgemeinschaft.
About the Institute of Molecular Biology gGmbH
The Institute of Molecular Biology gGmbH (IMB) is a centre of excellence in the life sciences that was established in 2011 on the campus of Johannes Gutenberg University Mainz (JGU). Research at IMB focuses on the cutting-edge fields of epigenetics, genome stability, ageing and RNA biology. The institute is a prime example of successful collaboration between a private foundation and government: The Boehringer Ingelheim Foundation has committed 154 million euros to be disbursed from 2009 until 2027 to cover the operating costs of research at IMB. The State of Rhineland-Palatinate has provided approximately 50 million euros for the construction of a state-of-the-art building and is giving a further 52 million in core funding from 2020 until 2027. For more information about IMB, please visit: www.imb.de.
Boehringer Ingelheim Foundation
The Boehringer Ingelheim Foundation is an independent, non-profit organization that is committed to promoting the medical, biological, chemical, and pharmaceutical sciences. It was established in 1977 by Hubertus Liebrecht (1931–1991), a member of the shareholder family of the Boehringer Ingelheim company. Through its funding programmes Exploration Grants, Plus 3, and Rise up!, the Foundation supports excellent scientists during critical stages of their careers. It also endows the prestigious Heinrich Wieland Prize and awards for emerging scientists. Additionally, it funds institutional projects combining AI and biomedicine, such as the AITHYRA institute in Vienna and a new research unit at the Center for Systems Biology in Dresden (BioAI Dresden). Other supported institutions include the Institute of Molecular Biology (IMB) in Mainz and the European Molecular Biology Laboratory (EMBL) in Heidelberg, both in Germany.
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