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Saturday, April 20, 2024

UC Davis researchers find key tool in chromosome crossovers

Researchers at UC Davis have discovered a key tool they believe helps sperm and eggs develop exactly 23 chromosomes each. This work, which could lead to significant insight into fertility as well as spontaneous miscarriages, cancer and other developmental disorders, was published on April 13 in the journal Cell.

Normally, if all goes according to plan, a human fetus develops into a healthy adult with exactly 46 chromosomes — 23 from the sperm and 23 from the egg. But just one small mistake in this process can have significant effects on the fetus, often developing into well-known disorders such as Down syndrome, which is caused by an extra copy of chromosome 21.

The developing process of a human fetus is complex, involving a multitude of processes, enzymes and other complexes that work together as one big unit. Because of its direct effect on many diseases, much research has gone into understanding this mechanism.

“We are trying to understand how these proteins work together at a molecular level and how they are regulated to do the right thing at the right time,” said senior author of the study Neil Hunter, a professor of microbiology and a member of the UC Davis Comprehensive Cancer Center research program.

During meiosis, the sexual cell division that produces sperm and eggs, matching chromosomes pair up and connect through a process known as “crossing over” — much like when two long strands of spaghetti twist together when twirled with a fork.  These crossover connections play an important role in creating sperm and eggs with exactly the right number of chromosomes.

According to Shangming Tang, a graduate student working in Hunter’s lab, each pair of chromosomes must contain at least one crossover. However, more than two crossovers per pair could damage the genome’s structure. Although scientists understand the need for chromosome crossover, research into understanding the mechanisms and enzymes through which this process occurs is only recently emerging.

“Knowing how each major pathway in meiosis is regulated will help us understand why certain syndromes occur and possibly how we can prevent or treat them,” Tang said.

In their study, Hunter and his research associates looked for enzymes that could cut DNA to form crossovers in yeast. Just like humans and other mammals form sperm and eggs, yeast form sexual gametes called spores. Through this experiment they discovered three yeast enzymes – Mlh1, Mlh3 and Sgs1 – which work to cut DNA and form crossovers.

From previous research, Hunter and his colleagues were aware of other enzymes that work together with these three. In a paper published last year, they described the discovery of enzyme Exo1, a type of enzyme called a nuclease, which is responsible for degrading DNA strands. According to Hunter, these yeast enzymes directly correlate with human enzymes; by analyzing these correlations, conclusions can be drawn.

“The human equivalents of Sgs1, Exo1, Mlh1 and Mlh3 are all tumor suppressors. What we are learning about their molecular functions is relevant for understanding what goes wrong in cancer,” Hunter said.

Hunter hopes this new discovery will help improve knowledge of certain diseases.

“Our fundamental discoveries are broadly relevant for understanding the problems that lead to various cancers, infertility, pregnancy miscarriage and [various] chromosomal diseases,” Hunter said. “We are eager to define the roles of [all] the cofactors found. So, we still have a lot to learn.”

CLAIRE MALDARELLI can be reached at science@theaggie.org.

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