Scientists Watched Two DNA Double Helices ‘Zip’ Together for the First Time

Metal ions may help DNA molecules overcome their mutual electrical repulsion.

DNA molecules should repel one another because their backbones carry the same negative charge.

Yet inside cells, DNA routinely has to approach and recognize other DNA. That happens during processes such as genetic recombination, chromosome organization and gene regulation. Something is clearly up and scientists have long suspected that charged ions help overcome the repulsion, but they had never directly seen the mechanism.

Now researchers at the Universities of Sheffield and York have imaged two DNA double helices aligning side by side, their grooves matching up precisely. Computer simulations suggest that positively charged metal ions form tiny bridges between the molecules, effectively helping them “zip” together.

These are the first direct structural images of DNA double helices joining together, supporting a mechanism proposed roughly 25 years ago, known as the electrostatic DNA zipper.

“To be able to directly visualise this long-hypothesised mechanism for the first time was incredible,” Thomas Catley, a co-lead author at Sheffield, said in a University of Sheffield news release.

A 25-year-old idea comes into focus

In 2001, theoretical physicists Alexei Kornyshev and Sergey Leikin proposed that ions gathering around DNA could alter its electrical landscape. Because DNA twists, those charges could produce a repeating pattern that allows suitably aligned helices to fit together electrostatically like interlocking spiral staircases.

Later experiments began to show that DNA may not always need proteins to find a matching stretch of DNA. In 2009, researchers observed long, similar DNA molecules pairing with each other on their own. Studies in the fungus Neurospora crassa then found that short matching sequences could help DNA line up, especially when those matches repeated at regular intervals along the helix.

More recently, researchers using a nanoscale sensor found that matching DNA molecules attract each other slightly more strongly when certain positively charged ions are present. Together, these studies revealed that matching DNA molecules may be able to line up partly because of the physical structure and chemistry of the DNA itself.

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What’s new now is that we finally have a picture of the proposed geometry.

The researchers examined DNA in liquid with nickel, calcium or magnesium ions. They used high-resolution atomic force microscopy to image the molecules. In their clearest images, neighboring helices lined up major groove with major groove and minor groove with minor groove — precisely the arrangement the zipper model predicts.

Across larger sets of 339-base-pair DNA fragments, about 10 to 14 percent appeared paired, typically remaining in contact for roughly 14 to 16 nanometers, or about three to four turns of the helix. Those overall rates did not differ significantly among the three ions.

Tiny ions form molecular bridges

The computer simulations revealed that divalent ions — atoms carrying two positive charges — could lodge around DNA and interact with both helices at once, partly neutralizing the repulsion between their negatively charged backbones.

Nickel ions appeared to help certain stretches of DNA stick together more strongly than others. In the simulations, one short sequence called GTAC repeatedly became a particularly stable meeting point between the two DNA molecules. Calcium and magnesium could also hold DNA together, but they did so in a wider variety of ways.

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The researchers also found that DNA did not have to be a perfect match for two molecules to make initial contact. Many of the pairings they observed involved sections that were not fully matching.

That suggests the process may happen in two stages. Ions may first help bring two nearby DNA molecules together. If the sequences and shapes of those molecules match well enough, the contact can then become more stable and extend along the helix, rather like a zipper closing.

There is an important caveat. These were purified DNA molecules imaged on mica, not chromosomes inside a cell, and nickel was especially useful for obtaining the highest-resolution images. In simulations using more cell-like mixtures of potassium with magnesium or calcium, successful parallel pairing occurred only in a minority of runs.

So, the study does not show DNA zipping together unaided inside a living nucleus. It offers a physical mechanism that cells might exploit alongside proteins, molecular crowding and chromosome architecture.

“This discovery could help researchers identify regions of the genome specially involved in DNA pairing,” Agnes Noy, who co-led the research at York, said in the university’s news release. “These regions may become particularly important when mutations disrupt normal cellular processes and contribute to cancer.”

The findings appeared in the journal Nucleic Acids Research.