Mechanisms of surveillance and repair of retrotransposon-mediated DNA damage in arrested and aging oocytes

• Applicants: Professor Dr. Volker Dötsch; Professor Dr. Björn Schumacher
• Subject Area: Reproductive Medicine, Urology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558166204

The integrity of the genetic information of oocytes is of paramount importance for the development of an individual as well as for the genetic quality of all species. It is threatened both by extrinsic as well as intrinsic agents. While extrinsic agents such as ionizing radiation and chemotherapeutics cause serious problems in patients treated for tumors or autoimmune diseases (infertility), all females are affected by age-related deterioration of the genetic quality by intrinsic processes. One of these processes is the reactivation of retrotransposons. It was recently discovered that oocyte lose epigenetic marks during aging, which leads to increased retrotransposon activation and DNA damage in all stages of oocyte development in aging individuals. As the age of mother continues to increase, investigating the mechanisms of retrotransposon activation triggered DNA damage and DNA repair is of high importance for improving quality and safety of in vitro fertilization (IVF) procedures. While many molecular details of the surveillance of the genetic quality in young primary oocytes arrested in prophase of meiosis I have been described in the past (the TAp63a-based monitoring system), not much is known about how aging oocytes react to and combat the activation of retrotransposons and the consequential DNA damage. In this grant application we propose to investigate the interplay between DNA integrity surveillance and DNA repair in aging oocytes. In particular, we will study how retrotransposon-mediated DNA damage is sensed by the TAp63a and p53 surveillance systems and downstream DDR machinery in aging mammalian oocytes, use the power of the C. elegans model organism to identify regulatory mechanisms of transposon activation in aging oocytes and explore possible pharmacological and genetic interventions to manipulate retrotransposon-mediated damage. Through the collaboration of the three groups of this grant application we combine expertise in biochemistry and mechanistic cell biology with mouse and C. elegans animal models.

• DFG Programme: Research Grants
• International Connection: Israel
• International Co-Applicant: Professor Dr. Michael Klutstein, Ph.D.