Early in the development of sperm, a strange event happens: the X and Y chromosomes condense into tight packages and are sequestered away from the other 44 human chromosomes. If any part of this process goes awry, the cells cannot mature into sperm. Researchers in the UC Davis College of Biological Sciences have now identified an important link in this process—a little-known protein called ATF7IP2.
“This could be a critical factor for ensuring male fertility,” said Satoshi Namekawa, professor of microbiology and molecular genetics, whose team contributed to the new findings. Their results, published in Genes & Development, could help elucidate the causes of male infertility.
A dangerous moment for DNA
The discovery sheds light on a pivotal moment in the production of sperm that is necessary for the health of our species—but also potentially dangerous.
The cells that give rise to sperm contain 46 chromosomes—two copies each of chromosomes 1 through 22, plus one of each sex chromosome, X and Y. The sperm will eventually carry only half a set—23 chromosomes, including either X or Y. Before they are divided up, the 22 sets of homologous chromosomes pair up, and segments of DNA are swapped between each pair. This recombination shuffles the genetic deck, ensuring that the next generation of humans will have diverse genes that determine disease resistance and many other traits.
But recombination carries risks. The DNA must be cut and rejoined dozens of times without a single error. If the wrong chromosomes are paired up, the wrong cuts are made, or the wrong ends are rejoined, the resulting embryo may fail to develop, or the offspring may end up missing genes, or with extra copies, triggering genetic diseases.
Namekawa and his team have spent years studying the way that germline cells (which produce sperm and egg cells) prevent this from happening. They and others have found that a constellation of proteins called the DNA damage response (DDR) guides the process. When a person is exposed to radiation, chemicals, or anything else that breaks DNA, the DDR ensures that the resulting loose ends are correctly reattached. DDR plays a similar role in recombination, making sure that chromosomes only pair up with their twins and that cuts are rejoined.
But unlike other pairs of chromosomes, X and Y are actually different from one another. If they swap parts, this could damage the genome, said Kris Alavattam, a former doctoral student in Namekawa's lab, now at the Fred Hutchinson Cancer Center in Seattle.
“When X and Y are unable to match up, the DDR causes them to come together into their own compartment, away from the other chromosomes,” he said.
This happens when an enzyme called SETDB1 modifies the protein spools that the X and Y chromosomes' DNA is wrapped around, causing it to coagulate into a dense structure called heterochromatin. The resulting inactivation prevents recombination and silences the X's and Y's genes at the correct time to prevent them from interfering with the process of divvying up chromosomes into sperm cells.
Source: UC Davis