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The DNA replication origin recognition complex (ORC) is a six-protein machine with a slightly twisted half-ring structure (yellow). ORC is proposed to wrap around and bend approximately 70 base pairs of double stranded DNA (red and blue). When a replication initiator Cdc6 (green) joins ORC, the partial ring is now complete and ready to load another protein onto the DNA. This last protein (not shown) is the enzyme that unwinds the double stranded DNA so each strand can be replicated. | Illustration courtesy of Brookhaven Lab.
In the beginning . . . but how do you begin?
That question has long perplexed scientists in fields from cosmology to anthropology. Fortunately, researchers at Brookhaven National Lab are beginning to get at the answer on a small, but important scale . . . in biology.
Specifically, the researchers looked at how cells duplicate their DNA and replicate themselves. DNA is the essential stuff of beginnings. Its double strands -- which consist of chemical ‘letters’ or base pairs -- tell cells how to remake themselves: how to build the protein machines that keep them alive and make them distinct. So before they divide, cells have to duplicate their DNA.
This is a relatively straightforward affair for bacteria (and other simple cells, also called prokaryotes) since they typically only have a single loop of DNA, even though it can be millions of base pairs long. As a consequence, they have just a single point along the strand where the copying starts, called an origin of replication.
Most of biology that can be seen with the naked eye -- animals and plants and even humble yeast -- is composed of more complicated cells called eukaryotes. Eukaryotes have much more DNA, which is tightly wound into distinct pieces, or spindles, called chromosomes, each of which may have many origins of replication. ‘Top gun’ cells, say those in humans, have a need for speed, since they have some 3.4 billion DNA base pairs, all of which have to be pulled apart and copied. So in order to finish in a reasonable amount of time, those cells have to begin copying their DNA simultaneously at tens of thousands of different points.
But how do they begin? Namely, how do protein machines find and bind to the right spots along the DNA strand, and then set them up for copying? That’s what the team at Brookhaven Lab studied. They used an imaging method known as cryo-electron microscopy to take extremely high resolution images of how the right proteins come together at the right point on the DNA strands, forming a structure called an “origin recognition complex” (ORC). The lab’s first-of-a-kind images (taken using yeast cells, which are also eukaryotes), showed how the shape of the complex changes as it sets the DNA up for duplication.
Scientists then gathered additional details about individual parts of the structure from previously made X-ray crystallography images, which showed the positions of many individual portions of the complex. Then they took all of their information and ran a detailed computer simulation, which gave scientists a good idea of how the whole process works.
That’s important since beginnings can go bad, and uncontrolled cell division is the hallmark of many cancers. The new insights from Brookhaven Lab might lead to new ways to attack cancers at a basic level, one reason that the National Institutes of Health also supported this research.
But there’s also a deeper reason to do basic research. Beginnings are one of the most precious opportunities of all, the chance to create, to discover. That’s what happens with each new experiment run at National Laboratories: Each day it’s a new chance to begin again . . . in the beginning.