Cryo-EM structures show how a second phage protein flips an integrase from inserting DNA to removing it
University of Chicago researchers used cryo-EM to capture large serine integrases at several stages of inserting and removing phage DNA. The Molecular Cell paper shows how a partner protein flips the enzyme from one job to the other.
The Scientist · Science desk
What happened
- In nature the integrase inserts viral DNA into a bacterial chromosome in one direction, and taking it out again needs a partner protein called a recombination directionality factor.
- The structures show part of the integrase acting as a movable arm that helps lock newly inserted phage DNA into place.
- To remove the DNA, the partner protein reshapes the enzyme, so insertion and removal run as two distinct processes.
- Large serine integrases do all of this without relying on the host cell's own DNA repair machinery.
Why it matters
- What's now possible capability The structures point to which parts of the proteins control activity and directionality, which gives engineers specific parts to change, according to the report on the work.
- What it limits constraint The damage-free claim comes from the senior author and is worded conditionally, so any engineered version still has to show it in mammalian cells.
- Who has to decide decision Rice's lab and Weixin Tang's already work on these enzymes in mammalian cells, so the structures can guide which parts that project alters next.
Directionality in these enzymes had been described for years without a picture of the switch [5]. The team's answer was cryo-EM, which freezes molecules rapidly and photographs them under an electron microscope at near-atomic resolution [8]. One image cannot show a change of state, so they captured multiple stages of both insertion and removal [1]. The switch is read from that series of stills. The paper, by Heewhan Shin and colleagues, is titled "Structural basis of directionality control in large serine integrases" and appeared in Molecular Cell in 2026 [2].
Phoebe Rice, the senior author, put the insertion half in one sentence. "The protein can assume a different shape when it's bound to the product, which traps it that way," she said [9]. Reversal needs outside help, and she described where it comes from: "But these phages can also pop back out of the host. So, they make a second protein that binds to the integrase protein, changes its shape again and then the reverse reaction happens" [10].
Researchers are already testing large serine integrases as genome-editing tools and as programmable genetic switches [12]. Rice's lab has been collaborating with Weixin Tang, an associate professor of chemistry at UChicago, on using them in mammalian cells [13]. The attraction is clean editing. "When they work like they're supposed to, they don't even leave a single nicked bond in the host DNA," Rice said [11].
That claim is conditional on the enzyme working as intended. A structure shows what the enzyme looks like at each stage, and it does not measure how often an engineered version works as intended in a mammalian cell.
The thing this doesn't tell you is how efficiently any engineered integrase edits mammalian cells. The account of the work describes structures, not editing results, and it does not say which integrase or phage was imaged. We'd expect the Rice and Tang collaboration to be where that gets tested.
What to watch
- Editing results from the Rice and Tang collaboration on large serine integrases in mammalian cells.
- Whether engineered integrases built from these structures still switch direction on demand outside the phage's natural system.
Clarity's read
What the record supports and how the coverage leans. The claims behind it follow.
Reality
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- Adoption
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- Hype gap+20
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- [1]
Researchers at the University of Chicago, led by senior author Phoebe Rice, a professor of biochemistry and molecular biology, used cryo-electron microscopy to see three-dimensional structures of the enzyme system, capturing multiple stages of both DNA insertion and removal.
- [2]
The study, by Heewhan Shin et al., titled 'Structural basis of directionality control in large serine integrases', was published in Molecular Cell (2026).
- [3]
Large serine integrases are enzymes that phages use to insert their DNA without relying on the host cell's own DNA repair machinery.
- [4]
In nature, an integrase first inserts viral DNA into a bacterial chromosome in one direction; to reverse the process and remove the DNA, the enzyme requires help from a partner protein known as a recombination directionality factor (RDF).
- [5]
Scientists have known about the reversal behavior for years but lacked detailed structural information explaining how the molecular switch works.
- [6]
The structures showed that part of the integrase acts like a movable arm that helps lock the newly inserted phage DNA into place.
- [7]
When it is time to remove the phage DNA, the RDF changes the enzyme into a different shape, so the enzyme uses two distinct processes depending on whether it is inserting or removing DNA.
- [8]
Cryo-EM is a technique that allows scientists to visualize biological molecules at near-atomic resolution by rapidly freezing them and taking a snapshot of them with an electron microscope.
- [9]
Rice said: "The protein can assume a different shape when it's bound to the product, which traps it that way."
- [10]
Rice said: "But these phages can also pop back out of the host. So, they make a second protein that binds to the integrase protein, changes its shape again and then the reverse reaction happens."
- [11]
Rice said: "When they work like they're supposed to, they don't even leave a single nicked bond in the host DNA."
- [12]
Large serine integrases are already being explored as tools for genome editing and programmable genetic switches.
- [13]
Rice and her lab have been collaborating with Weixin Tang, an associate professor of chemistry at UChicago, on using these enzymes for genome editing in mammalian cells.
- [14]
By revealing which parts of the proteins control activity and directionality, the study offers a roadmap for engineering improved versions tailored for biotechnology and medicine, according to the report.
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Sources
1 independent publisher whose own reporting we read for this story.
- phys.orgMolecular snapshots reveal how viral enzymes switch between inserting and removing DNA
1 article · October 15, 2026
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