„Genomic integrity of oocytes is essential for life“

Despite the importance of the integrity of the genome of germ cells as the blue print of the genetic information that is passed on to all progeny cells following fertilization, this genomic integrity is massively attacked by the action of Spo11. This enzyme creates hundreds of DNA double strand breaks (DSBs) per cell. These DSBs trigger the process of homologous recombination which enhances genetic variability and are also required for reliable chromosome segregation during cell division. SPO11 induced DSBs, however, are not the only threat to the DNA. In mammals, oocytes are characterized by another unusual characteristic: they are arrested in prophase of meiosis I for a very long time (up to ~50 years in humans) during which their tetraploid genome can accumulate damage. Moreover, epigenetic marks deteriorate during aging, which leads to increased retrotransposon activation and DNA damage, posing further risks to the oocyte genome.

All these traits render oocytes unique, and at the same time, require specialized quality control processes. Understanding the molecular mechanisms of how oocytes deal with genome insults and maintain genomic integrity, as well as, how these mechanisms are affected during aging are of key importance for reproductive health and this consortium will focus on two different aspects:

• Oocyte quality is crucially important for the success rate and safety of in vitro fertilization (IVF) and intracytoplasmatic sperm injection (ICSI) and is tightly linked to an oocyte’s age.
• The oocyte-specific quality control systems are responsible for the elimination of the pool of primary oocytes in female cancer patients treated with chemotherapy or ionizing radiation resulting in infertility and premature ovarian insufficiency. For female cancer survivors not only fertility is jeopardized, the loss of the pool of arrested primary oocytes also eliminates the endocrine function of the ovaries, resulting in a premature start of menopause which puts women at risk of suffering from diseases such as osteoporosis.

This consortium will study the basic molecular mechanisms of quality control and DNA repair in primary oocytes using model organisms and will translate the results to human ovarian tissue. One goal is to obtain a detailed understanding of the aging process in older oocytes. This necessitates investigating the molecular mechanisms that result in the breakdown of the epigenetic structure and the activation of retrotransposons as well as a mapping of the ensuing DNA damage. Another goal is to investigate the requirements of a potential fertiprotective therapy for female cancer patients. This requires, again, a detailed understanding of the molecular quality control mechanisms as well as characterization of the DNA damage caused by different therapeutic agents and the repair scars that remain if oocytes survive. These results will be integrated into the consultations of cancer patients by the consultation network FertiPROTEKT.