‘Missing tool’ enzymes match up chromosomes

Researchers have discovered a key tool that helps sperm and eggs develop exactly 23 chromosomes each, a finding that could lead to insights into fertility, cancer, and developmental disorders. Healthy humans have 46 chromosomes, 23 from the sperm and 23 from the egg. An embryo with the wrong number of chromosomes is usually miscarried, or develops disorders such as Down syndrome, which is caused by an extra copy of chromosome 21. During meiosis, the cell division process that creates sperm and eggs, matching chromosomes pair up and become connected by “crossing over” with each other, says Neil Hunter, a professor of microbiology at University of California, Davis and senior author of the new study. These connections are essential for precise chromosome sorting and the formation of sperm and eggs with exactly the right numbers of chromosomes. Crossovers also play a fundamental role in evolution by allowing the chromosomes to swap chunks of DNA, introducing some variety into the next generation. Each pair of chromosomes must contain at least one crossover. But there shouldn’t be more than about two crossovers per pair, or the genome could be destabilized. In their paper published in the journal Cell, Hunter and colleagues describe a “missing tool” that explains how crossovers are regulated. “There must be enzymes that ensure at least one crossover, but not too many,” said Hunter, who is also a member of the UC Davis Comprehensive Cancer Center research program. Hunter, graduate students Kseniya Zakharyevich and Shangming Tang, and research associate Yunmei Ma looked for enzymes that could cut DNA to form crossovers in yeast, which form sexual gametes, or spores, in much the same way that humans and other mammals form sperm and eggs. “There were several good candidates, but none turned out to play a major role,” Hunter said. Then they discovered the missing tool for crossing over: three yeast enzymes, Mlh1, Mlh3, and Sgs1, which work together to cut DNA and make crossovers. It turns out that the human equivalents of these enzymes are well known for their role in suppressing tumors. Human MLH1 and MLH3 are mutated in an inherited form of colon cancer. BLM, the human equivalent of Sgs1, is mutated in a cancer-prone disease called Bloom’s syndrome. “Sgs1 was the biggest surprise. We previously knew it as an enzyme that unwinds DNA to prevent crossovers. Its role in making crossovers had been hidden by other enzymes that can step in when it is absent,” Hunter says. “While other enzymes cut DNA randomly, Mlh1-Mlh3-Sgs1 only makes crossovers. This unique activity is essential for meiosis and its discovery is a huge step forward.” The work was supported by the National Institutes of Health. Hunter is an early career scientist of the Howard Hughes Medical Institute.