World of Reproductive Biology

A study in mice points to a new approach to preserving fertility in female cancer patients. Chemotherapy can wreak havoc on DNA. The drugs can damage the DNA of the oocyte pool, resulting in the induction of a cell-death program and culling of primordial oocytes, which provide a lifetime’s supply of eggs. A consequence of cancer therapy in women is often reduction of the ovarian reserve, resulting in impaired fertility and early menopause. Approaches to fertility preservation currently rely mainly on freezing oocytes or ovarian tissue prior to chemotherapy. But reproductive biologists have been seeking ways to protect oocytes from the effects of the chemotherapeutic agents by pharmacological means. The new study edges researchers closer to this goal. In this investigation, Jeffrey Kerr, Karla Hutt, Ewa Michalak, and colleagues took a close look at the triggers for oocyte death in response to DNAdamaging agents. Consistent with previous results, they found that DNA damage induces the activity of the transcriptional regulator TAp63, a homolog of Trp53—also known as p53, the famed ‘‘guardian of the genome.’’ The researchers also showed that TAp63 induced the expression of two factors that promote apoptosis, Puma and Noxa (both are members of the BH3-only pro-apoptotic subgroup of the wider BCL-2 family). Crucially, they showed that the primordial oocytes in mice lacking Puma or both Puma and Noxa were protected from apoptosis induced by DNA damage. These females could also produce apparently healthy offspring with no overt deformities and normal fertility. The mice lacking these genes also seemed to have active DNA repair pathways: A protein involved in double-stranded break repair (cH2AX) accumulated on damaged oocyte DNA in the oocytes of these mice, but was largely absent after five days, suggesting that the repair protein had done its job. It’s unclear whether the offspring suffer from damage to their DNA that might yield more subtle effects, and the researchers acknowledge the need for longer-term follow-up studies. If the same mechanism operates in humans, drugs that block PUMA and NOXA may be useful for preventing infertility in female cancer patients and could possibly even fend off menopause in healthy women. Kerr JB, Hutt KJ, Michalak EM, Cook M, Vandenberg CJ, Liew SH, Bouillet P, Mills A, Scott CL, Findlay JK, Strasser A. DNA damageinduced primordial follicle oocyte apoptosis and loss of fertility require TAp63-mediated induction of Puma and Noxa. Mol Cell 2012; 48(3):343–352.