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A Holliday junction is a fleeting four-way crossover that occurs between DNA strands of the two chromosomes that make up a pair, allowing the reciprocal exchange of genetic information during a process known as homologous recombination. This mechanism was first proposed in 1964, and so far, only proteins from prokaryotes — organisms whose cells lack a nuclear membrane — have been shown to promote the formation of this type of DNA structure. On page 1018, Hiroshi Iwasaki of Yokohama City University in Japan and his colleagues demonstrate that similar proteins from eukaryotic — or nucleated — cells from yeast and humans promote Holliday-junction formation. Iwasaki spoke to Nature about why he finds the Holliday junction so intriguing.
You have worked on Holliday junctions for the past two decades. Why?
Holliday-junction formation is dangerous for cells, because their DNA must be cut in order to be rearranged. But this step is necessary for all organisms, not only to generate genetic diversity, but to repair damaged DNA — for example, in double-strand breaks. I find this very interesting. In 1991, we identified an enzyme that disassembles the Holliday-junction structure in the bacterium Escherichia coli. After that, I was motivated to find such an enzyme in eukaryotic cells, because no one had yet done so.
Did you use a novel approach to do this?
Yes. DNA is polar, and in prokaryotes DNA-strand exchange proceeds in only one of two possible directions. We looked for DNA-strand exchange from both polarities in eukaryotes, and found that it runs in the opposite direction to that in prokaryotes. Without looking in both directions, we would not have found the protein activity responsible for eukaryotic strand exchange.
Is there more to learn about basic biological mechanisms?
Yes. Basic biological mechanisms can easily get overlooked in science, but they underlie so many processes. For example, induced pluripotent stem cells — which can develop into any of the body's cell types — obtained from skin cells are a hot topic at the moment, but the fundamental mechanism underlying their transformation from differentiated cells to stem-like cells is simply the regulation of transcription.
Where will your work go from here?
We still don't know the precise mechanisms by which a Holliday junction is formed and later disassembled by the enzymes we have identified. My goal is to uncover the entire mechanism of homologous recombination.
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Abstractions. Nature 451, xvi (2008). https://doi.org/10.1038/7181xvib
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DOI: https://doi.org/10.1038/7181xvib