New study has decoded the mechanism leading to premature loss of the oocyte pool caused by treatment with chemotherapy. The study led by Prof Volker Dötsch at the Institute for Biophysical Chemistry of Goethe University is published in the journal Nature Structural and Molecular Biology.
Many chemotherapeutics act by damaging the DNA. Since cancer cells divide more often than most normal cells, they react more sensitive to DNA damaging agents. One exception are oocytes. To prevent birth defects they initiate a cellular death program if DNA damage is detected. This process, called apoptosis, is triggered in oocytes by the protein p63. Oocytes contain a high concentration of an oocyte-specific isoform of p63 which plays a key role as a quality control factor in causing infertility .
In non-damaged oocytes p63 exists in an inactive form. DNA damage caused by chemo- or radiotherapy results in the modification of p63 with phosphate groups which triggers a conformational change to the active form. Active p63 starts the cell death program which leads to the elimination of the oocyte.
These results open new opportunities for developing a therapy for preserving oocytes of female cancer patients treated with chemotherapeutics. In experiments with mouse ovaries inhibiting the identified enzymes saved the oocytes from cell death despite treatment with chemotherapeutics.