Why aged oocytes struggle to repair DNA damage

Egg cells need stamina: They are formed in a woman's body before birth and have to be on standby for decades to possibly be fertilized one day. But as they age, they accumulate more and more DNA damage. Until now, it has been unclear why the cell's repair mechanisms do not fix the damage.

Researchers led by Melina Schuh and Ninadini Sharma at the Max Planck Institute (MPI) for Multidisciplinary Sciences have now shown in experiments with mice that aged egg cells repair their DNA less efficiently than young ones, and that repair becomes more error-prone with advancing maternal age.

Cells in the human body have very different life spans, depending on their type and function. Skin cells renew themselves every two to four weeks. Liver cells can last up to 500 days. Egg cells are particularly long-lived: they are created in the female body even before birth and do not renew themselves. Thus, a 30-year-old woman has egg cells that are just as old.

The egg cell's ability to repair damage in its DNA is crucial to ensure that it remains functional for a long time and does not die. To this end, egg cells have developed a complex repair machinery with different repair pathways.

In all these pathways, special proteins detect changes in the DNA and repair them. This machinery is also responsible for repairing DNA damage that occurs in the father's sperm and in the developing embryo. Despite the presence of multiple DNA repair mechanisms, unrepaired DNA damage accumulates in aging egg cells. Until now, it has been unclear why this happens.

Less efficient and error-prone repair

A research team led by Max Planck director Melina Schuh, head of the Department of Meiosis at the MPI for Multidisciplinary Sciences, has now compared young and aging egg cells in terms of their DNA damage and DNA repair machinery. The research is published in the journal Current Biology.

Using high-resolution fluorescence microscopy, her team determined the amount of DNA damage in human and mouse egg cells of different ages, mapped important repair proteins in the cell nucleus, and analyzed how their activity and interactions change with age. "We found that DNA repair slows down in aged oocytes," says Schuh. "As a result, DNA damage accumulates in the cell."

A changing repair network

To better understand the repair machinery of egg cells, the researchers created a "map" of the most important repair proteins in the egg cell's nucleus. This map showed that DNA repair proteins are located in specific compartments of the egg cell.

"These compartments are interconnected or located close to each other, suggesting coordinated assembly and activity" explains Ninadini Sharma, a former doctoral student in Schuh's department and first author of the study.

"DNA repair compartments change substantially with age, for example, their number, morphology and response to DNA damage," adds Sharma. "Error-prone repair pathways are used more frequently, while error-free pathways become less efficient."

Cohesin loss increases DNA damage

In addition to these changes, the researchers identified another reason for increased damage in aged egg cells: The amount of the protein cohesin decreases with increasing maternal age, leading to chromosome segregation errors. Cohesin holds sister chromosomes together until they are ready to separate during cell division.

At the same time, the protein is essential for DNA repair: If a strand of DNA is broken, for example, it ensures that the damaged part can be repaired using an intact DNA strand as a blueprint.

But it is not only aging egg cells that are affected by cohesion loss. "Interestingly, reduced cohesion also led to higher levels of DNA damage and slower DNA repair in young egg cells," reports Schuh. "Apparently, it is not only the slower, more error-prone repair machinery but also the decline in cohesin with age that promotes accumulation of DNA damage and death of aged egg cells."