Shirleen Roeder's lab group characterized a protein that zips matching chromosomes together during meiosis.

Barbara Meyer, an HHMI investigator at the University of California, Berkeley, focuses on understanding how some X chromosomes are normally regulated in females, and her research has begun to intersect Keeney's work. She has found that a mutation affecting proteins that repress the X chromosomes also affects how many double-strand breaks are made, and their locations, during meiosis. Meyer thinks that the overall structure of chromosomes, including how compact they are, influences both double-strand breaks and X chromosome repression.

“These very different processes seem to have in common that changes in higher-order chromosome structure mediate how and where the biochemistry happens,” she says.

Even if Keeney and Meyer can pinpoint where double-strand breaks are made, scientists have no shortage of questions about the next stage of meiosis. Full of double-strand breaks, chromosomes need to pair up with their homologues, repair the breaks, trade some larger bits of genetic material, and then separate.

Shirleen Roeder and Nancy Kleckner both want to know how matching chromosomes find each other and associate while exchanging bits of DNA.

In 1993, Roeder's Yale University lab group characterized a protein, appropriately named Zip1, which acts like a zipper between matching yeast chromosomes. “They look like railroad tracks lined up connecting the chromosomes,” says Roeder of the proteins. To show that Zip1 was linking chromosomes, a graduate student in Roeder's lab toyed with the length of the Zip1 protein. The result: longer Zip1 proteins spread matching chromosomes farther apart, while shorter proteins drew the chromosomes closer together. “It was just the coolest thing!” says Roeder.

In the decade and a half since, Roeder has discovered a handful of additional components of the structure known as the synaptonemal complex, or SC, which includes Zip1 and holds chromosomes together. Each round of discoveries about how the SC assembles has surprised her, Roeder says.

First, her team found that in mutants that can't undergo recombination—the exchange of genetic material between homologues—Zip1 doesn't zip up the chromosomes but instead appears at a single point: the centromere. Moreover, the linked chromosomes in these mutants aren't necessarily even matches.

“This initially was so surprising to us that we thought there must be something wrong with our experiments,” says Roeder. But the results were confirmed. Roeder's interpretation is that the Zip1 dots act more like worn-out Velcro than zippers—they disconnect easily and are a normal part of how a chromosome finds its mate. Two chromosomes come together, make this weak connection at the centromere, and then separate if they're not matches. If they are matches, Zip1 can zip them together.

Photo: Lisa Kereszi

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