Image by Kimberly Carney / Fred Hutch News Service
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.”
Image by Kimberly Carney / Fred Hutch News Service
An 88-year-old mystery
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.”
A centromeric traffic cop
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.
Fred Hutch file
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 properl