Researchers at the MRC Laboratory of Medical Sciences (LMS) and collaborators have identified one of the earliest steps in DNA replication: the moment a cell first opens its DNA to begin copying its genome. Published in Nature Communications, the findings reveal where DNA first unzips inside living cells and identify a molecular gate that prepares DNA for copying.
Every time a cell divides, it must copy its entire genetic instruction manual, making DNA replication one of biology’s most tightly controlled processes. Before copying, cells activate helicases, machines that separate the two DNA strands. A six-subunit complex called MCM2-7 forms a pair of rings around DNA at replication origins; once activated, the rings split apart to form the core of the two emerging replication forks.
Scientists had long struggled to observe how this process begins inside living cells, leaving open questions about where DNA first opens and how one strand exits the helicase ring.
“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 machine 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,” said senior author Maximilian Reuter.
Using synthetic biology, genome-wide DNA mapping, and protein analysis in living yeast cells, the team found DNA begins opening near where the two MCM2-7 rings meet—the same region used earlier to recruit the proteins that start replication.
The researchers also identified a specialized gate within the helicase complex, a doorway through which one DNA strand exits as the machinery activates. The study linked DNA opening, helicase separation, strand release, and the arrival and departure of replication proteins into a single framework, capturing previously unseen intermediate states. Many of the proteins involved are conserved from yeast to humans, suggesting the findings could apply broadly.
“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,” said co-senior author Christian Speck.
Every time a cell divides, it must copy its entire genetic instruction manual, making DNA replication one of biology’s most tightly controlled processes. Before copying, cells activate helicases, machines that separate the two DNA strands. A six-subunit complex called MCM2-7 forms a pair of rings around DNA at replication origins; once activated, the rings split apart to form the core of the two emerging replication forks.
Scientists had long struggled to observe how this process begins inside living cells, leaving open questions about where DNA first opens and how one strand exits the helicase ring.
“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 machine 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,” said senior author Maximilian Reuter.
Using synthetic biology, genome-wide DNA mapping, and protein analysis in living yeast cells, the team found DNA begins opening near where the two MCM2-7 rings meet—the same region used earlier to recruit the proteins that start replication.
The researchers also identified a specialized gate within the helicase complex, a doorway through which one DNA strand exits as the machinery activates. The study linked DNA opening, helicase separation, strand release, and the arrival and departure of replication proteins into a single framework, capturing previously unseen intermediate states. Many of the proteins involved are conserved from yeast to humans, suggesting the findings could apply broadly.
“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,” said co-senior author Christian Speck.