A team at Fred Hutchinson Cancer Research Center has solved an 88-year-old mystery: how cells shield a specific segment of DNA so that sex cells — eggs or sperm in humans — end up with the right number of chromosomes.
Published Thursday in Molecular Cell, the work, done in fission yeast, reveals that a certain protein acts a like a traffic cop. This traffic-cop protein shields a key region of DNA from the wrong molecules while ushering the right ones over. The findings shed light on what may have gone awry when cells end up with too many or too few chromosomes, which can lead to spontaneous miscarriage or certain developmental disorders.
Swi6, the protein in question, “is a key regulator,” said senior author Dr. Gerald Smith, who worked with first author Dr. Mridula Nambiar to outline Swi6’s dual roles in proper chromosome sorting. “Mridula’s critical insight was that it has both positive and negative roles.”
Smith and Nambiar’s work unravels a longstanding mystery involving a process known as recombination.
DNA is stored in long strings called chromosomes, and as sex cells form, chromosomes form structures called crossovers that connect the chromosomes from each parent. Recombination happens when these overlapping parts of the two chromosomes trade bits and pieces of DNA. It’s an essential event that helps cells end up with the right amount of DNA after they’ve divided.
Crossovers along chromosome arms “hold mom and dad chromosomes together, so that when they begin to separate from each other, in opposite directions, there’s a tension built up,” explained Smith. “Without tension, they just wander around. Sometimes they go properly, but half the time it doesn’t work if you don’t have a crossover.”
It’s equally critical that DNA trading does not occur in the center of chromosomes. Recombination here also leads to mis-sorted chromosomes.
The implications in humans for mis-sorting chromosomes are clear. About 15 percent of recognized pregnancies end in miscarriage, and chromosomal abnormalities appear to be the cause in about half of these cases. Mis-sorted chromosomes also underlie developmental disorders such as Down syndrome. And cancer cells, known for their genetic disarray, often lose or gain chromosomes.
It’s been known since 1930 that cells protect this central region, or centromere, from recombination — but it’s taken nearly 90 years to discover how.
That’s because most other scientists had dismissed the question. They claimed that chromosomes’ middles, where DNA is especially densely packed, were simply inaccessible.
“But … to say it’s inaccessible because it’s condensed makes no sense,” said Smith, noting that genes in these tightly coiled regions get turned on, which requires the DNA to be accessed, and that other proteins responsible for keeping chromosomes attached to each other during sex-cell formation reach the DNA at centromeres just fine: “To say it’s inaccessible is just ignoring the facts in front of your face.”
Determined to solve the riddle of how cells prevent recombination from occurring in one chromosome location while encouraging it in another, Nambiar and Smith turned to fission yeast. Like humans and most other species, fission yeast protect their centromeres from recombination. A favorite model for researchers, fission yeast are relatively easy to manipulate genetically, and quicker and easier to study than more complex species like mice or people.
One by one, Nambiar examined genes known to be involved in sorting chromosomes and recombination during sex-cell formation. She discovered that yeast have evolved a two-layer strategy to protect regions close to the centromere from recombination, orchestrated by the Swi6 protein. (The human counterpart to Swi6 is a protein called heterochromatin protein 1, or HP1.)
During sex-cell formation, two different large molecular machines, each made of multiple proteins, keep chromosomes properly attached to each other. One binds near the centromere and connects replicated chromosomes. The other binds to chromosome arms, where it coordinates recombination between maternal and paternal chromosomes.
Swi6 protects centromeres from recombination by letting the right proteins in to form the complex that attaches near the centromere while keeping the riffraff out. In this case, the riffraff is a specific protein that activates the complex responsible for recombination.
Swi6’s dual nature was difficult to clarify because of a completely counterintuitive observation: Removing Swi6 from the cell doesn’t result in more recombination near the centromere. This is because one of the proteins that Swi6 ushers in is found in both complexes and is required for recombination — but it relies on Swi6 to arrive at the centromere. Without Swi6, even if other proteins in the recombination complex get through, they lack this critical component and recombination still can’t go forward.
“Swi6 has both positive and negative roles,” said Smith. “Because of the strong negative role, you don’t get recombination. But if you take Swi6 away, you’ve lost the negative role but also the positive role, so you [still] don’t get recombination.”
The two-pronged strategy for preventing recombination near the middle of chromosomes “makes very good biological sense,” Smith said. “If you have something you really don’t want to do, you don’t put one lock on it, you put two.”
He expects that many other species besides yeast use a very similar strategy and even the same basic proteins. Mammals have versions of the same proteins that form those crucial molecular complexes, and what’s known about them so far syncs with what’s known about their fission yeast counterparts.
Smith doesn’t suggest that these similarities mean that his and Nambiar’s insights will quickly lead to new treatments for human patients, but he does point out that understanding how cells regulate the all-important process of sorting their chromosomes is the first step to understanding what goes wrong and what to do about it. Many advances in medicine, such as the recent progress in cancer immunotherapy, are built on foundations laid by basic scientists decades ago, he noted.
“Medicine in general is enabled by basic science,” Smith said.
This study was funded by the National Institutes of Health.
Sabrina Richards, a senior editor and writer at Fred Hutch Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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