Our genome is particularly densely packed in human sperm: 23 strands of DNA with a total length of around one meter are stuck in a head with a diameter of only three-thousandths of a millimeter. For this purpose, the DNA is wrapped around certain proteins, so-called protamines. To better understand the role of these molecules, researchers have now bred mice that are defective in one type of protamine. In these animals, the DNA could not be packaged correctly in the sperm head, and the male mice were infertile. The results may also help to explore causes of infertility in human males.
In the cell nuclei of our body, our genetic material forms a compressed but still relatively loose ball: like a string of pearls, the long DNA threads are wrapped around specific packaging proteins, the histones. For reproduction, however, the paternal genetic information has to be further compressed in order to fit into the tiny head of the sperm. A different type of packaging protein is used here: The so-called protamines attract the DNA strongly and thus enable the strands of genetic material to wrap particularly tightly around them – a process that biologists call hypercondensation.
On the trail of sperm development
“Most mammals seem to produce only one type of protamine, PRM1,” explains Lena Arévalo from the University Hospital Bonn. “It’s different in humans, but also in rodents like mice – they also have a second type, the PRM2.” Together with her team, Arévalo has now researched the PRM2 in more detail. “In contrast to PRM1, PRM2 is formed as a precursor protein,” the researchers explain. Part of this precursor protein, called cP2, is gradually cut off during sperm development. The remaining part, so-called mature PRM2, then interacts with the DNA and, together with PRM1, mediates the hypercondensation.
“Removal of the cP2 domain is thought to be essential for proper condensation, but the role of cP2 is not clear,” the researchers said. To find out more about the function of this cleaved piece of protein, they bred mice that they genetically modified so that they lacked the cP2 domain and only produced the mature part of PRM2 directly. It turned out that sperm development was disturbed in the male mice without cP2. The animals were sterile.
disruptions in the packaging process
An important process that only runs incorrectly without cP2 is the transition of DNA from histones to protamines. Transition proteins are normally used here – but without cP2, the interactions between histones, transition proteins and protamines are apparently disrupted. “In addition, the compression of the genome in mice without cP2 seems to take place too quickly, so that the DNA threads break or are otherwise damaged,” reports Arévalo. The researchers want to conduct further studies to find out whether similar problems also occur in human men and whether protamine defects could be a reason for male infertility.
“There are only a few groups that analyze the role of protamines in hypercondensation,” says Arévalo’s colleague Hubert Schorle. “We are the only laboratory in the world to date that has succeeded in breeding mouse lines that can be used to specifically study specific defects in both PRM genes. This allows us and others to further explore the processes involved in sperm formation.”
Source: Lena Arévalo (University Hospital Bonn) et al., PLOS Genetics; doi: 10.1371/journal.pgen.1010272