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 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.
Photo courtesy of the Smith Lab
“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.”
A foundation for the future
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