A clearer picture of DNA repair

The thought of your chromosomes breaking may send shivers down your spine. But for developing egg or sperm cells, it’s essential.

In her laboratory, Lexy von Diezmann, a new College of Biological Sciences faculty member, studies a mechanism that repairs programmed breaks in chromosomes during meiosis, a form of cell division that occurs only in the production of eggs and sperm.

During meiosis, chromosomes undergo “crossing-over,” in which they break, exchange pieces, and repair the breaks. Evolution has conserved this repair mechanism for eons, as it is vital to fertility in many organisms, including humans and our fellow mammals.

Von Diezmann’s guide to the repair system is a protein called ZHP-3. When linked to a fluorescent molecule, it becomes visible through a special microscope setup. Von Diezmann watches in real time as ZHP-3 zips around chromosomes of a nematode worm—a frequent model for human gene activity—helping them heal the breaks.

“You can see these individual glowing spots as they move around, kind of like fireflies, and watch their trails as they go through this dark environment,” she says. “The process of crossover repair is beautiful!”

Crucial chromosomal mix and match

Through crossing-over, many of the chromosomes in our eggs or sperm acquire new combinations of genes that will be passed to our offspring. This contributes to genetic diversity in the population and gives evolution new material to work with.

Normally, every person has two copies of each chromosome: a “maternal” copy from mom and a “paternal” copy from dad. To avoid  delivering a double load of chromosomes, eggs and sperm carry one copy of each. Therefore, as these cells are produced, the number of chromosomes is cut by half—but not by simply discarding one copy.

Instead, chromosomes hedge their bets by exchanging parts during meiosis, the special form of cell division that produces eggs and sperm. This gives each chromosome a good chance that at least some of its genes will be passed on.

The accompanying graphic summarizes the process of meiosis. Some background follows.

Why we’re all unique

During normal cell division (mitosis), each chromosome creates a copy of itself. The two copies, now called chromatids, form a double chromosome held together at one location. When the cell divides, the connection breaks, the two chromatids are pulled apart, and each becomes a chromosome in one of the two “daughter” cells.   

But meiosis consists of two cell divisions. In the first, each doubled chromosome is paired with its paternal or maternal counterpart, forming a complex of four chromatids. Then one maternal and one paternal chromatid break at exactly the same location and switch the “severed”segments. This can be repeated at more than one location, always between the same two chromatids.

The cell then divides, separating the double maternal and paternal chromosomes into different daughter cells. Only this time, one maternal chromatid contains “paternal” DNA and vice versa.

In the second meiotic division, the daughter cells divide as in mitosis, separating the chromatids of each doubled chromosome into new daughter cells.

The end result is four cells. Each maternal and paternal chromosome will now exist as an intact copy in one of them and a partial copy in two others. Without the crossing-over of meiosis, every chromosome would have a 50-50 chance of being completely eliminated.

“You can think of meiosis as a mechanism to inherit [particular forms of genes] from all four grandparents,” von Diezmann observes.

Crossing-over can produce novel combinations of traits. For example, consider genes for eye and hair color on the same chromosome. Crossing-over can break this linkage, allowing a blue-eyed, blond man and a brown-eyed, brunette woman to have a child with brown eyes and blond hair.

Also, “Without crossovers, ‘good" genes next to ‘bad’ genes would remain linked, but crossovers allow them to be separated,” von Diezmann says.

One BIG sex difference in timing

In the egg cell destined to become you, crossing-over happened when your mother was an approximately 6-month-old fetus. That cell finished its first meiotic division when she reached puberty and its second when it was fertilized at your conception.

This means that in women, meiosis can take up to 40-50 years. In men, meiosis begins with puberty, takes about three days, and continues throughout life.

Clever chromosomes

“I'm fascinated by how chromosomes coordinate crossover events along their length,” von Diezmann says. “Not only does each chromosome always undergo at least one crossover, but when more than one crossover forms, they are spaced apart farther than you would expect by chance. We call this process "crossover interference," and it implies there is a signal that is transmitted millions of base pairs along the chromosome pair.

“My work aims to understand what designates breaks to form crossovers, and the physical mechanisms by which interference works.”