Cell and Developmental Biology Seminar Series

10604 1511368418

Cell and Developmental Biology Seminar Series: Mechanism of p63-based genetic quality control in oocytes

  • Datum: 06.12.2017
  • Uhrzeit: 13:30 - 14:30
  • Vortragender: Prof. Dr. Volker Dötsch
  • Institut für Biophysikalische Chemie, Goethe Universität, Frankfurt
  • Ort: Max-Planck-Institut für biophysikalische Chemie (MPIBPC)
  • Raum: AI building, large seminar room
  • Gastgeber: Hosted by Prof. Dr. Blanche Schwappach, University Medical Center Göttingen Dept. of Molecular Biology in cooperation with the Department of Meiosis, MPI BPC
  • Kontakt: tommaso.cavazza@mpibpc.mpg.de
The survival rate of cancer patients is steadily increasing due to better and more efficient therapies. These advances in cancer therapy, however, create a new and increasing problem since treatment with chemotherapeutic drugs and radiation increases the risk of premature ovarian insufficiency (POI) for female cancer patients. While assisted reproductive technologies can address the problem of infertility, these measures cannot restore the hormonal functions pivotal for women’s health. A more detailed understanding of the molecular mechanisms of therapy-induced POI could identify targets for pharmacological prevention of POI during gonadotoxic therapies. Loss of the primordial follicle reserve is the most important cause of POI, with the p53 family member p63 being responsible for DNA damage induced apoptosis of resting oocytes in the mouse. Oocytes express the longest isoform, TAp63a, which in resting oocytes adopts a closed, inhibited and only dimeric conformation. Detection of DNA double strand breaks, initiated e.g. by irradiation or chemotherapeutics, activates a kinase cascade that leads to phosphorylation of TAp63α by the priming kinase CHK2. This triggers the recruitment of the executioner kinase CK1 that adds four more phosphorylation sites. Disruption of an inhibitory β-sheet by electrostatic repulsion leads to the formation of open and active tetramers that initiate the expression of PUMA and NOXA resulting in the induction of apoptosis in the damaged oocyte. Inhibition of CK1 rescues oocytes of the primordial follicles from doxorubicin and cisplatin induced cell death, thus uncovering a new target for the development of fertoprotective therapies.

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