Abstract
The production of haploid gametes through meiosis is central to the principle of sexual reproduction. The genetic diversity is further enhanced by exchange of genetic material between homologous chromosomes by the crossover mechanism. This mechanism not only requires correct pairing of homologous chromosomes but also efficient repair of the induced DNA double-strand breaks. Oocytes have evolved a unique quality control system that eliminates cells if chromosomes do not correctly align or if DNA repair is not possible. Central to this monitoring system that is conserved from nematodes and fruit fly to humans is the p53 protein family, and in vertebrates in particular p63. In mammals, oocytes are stored for a long time in the prophase of meiosis I which, in humans, can last more than 50 years. During the entire time of this arrest phase, the DNA damage checkpoint remains active. The treatment of female cancer patients with DNA damaging irradiation or chemotherapeutics activates this checkpoint and results in elimination of the oocyte pool causing premature menopause and infertility. Here, we review the molecular mechanisms of this quality control system and discuss potential therapeutic intervention for the preservation of the oocyte pool during chemotherapy.
Highlights
Quality control processes are essential for every aspect of cellular function
Experiments with mice have demonstrated a direct connection between the expression of TAp63α and the induction of apoptosis following double-strand breaks (DSBs): γ-irradiation with 0.45 Gy resulted in the elimination of virtually all primary oocytes, while secondary and antral oocytes, which do not express p63, survive [20]
In vitro fertilization of TAp73−/− oocytes resulted in high numbers of embryos with multinucleated blastomeres and in blastocysts with an abnormal cell number. These results suggested a link between TAp73 and the spindle assembly checkpoint, which regulates the correct attachment of sister chromatids both to the mitotic and meiotic spindle [106]
Summary
Of particular importance is the surveillance of the genetic information stored in the DNA, as mutations can have severe consequences ranging from dysfunctional cells to the development of cancer This genetic information is under constant threat from errors in the replication process, from the action of transposons as well as from chemical modifications or irradiation-induced damage. The most dramatic effects occur in germ cells, with all cells of the developing body and all subsequent offspring being affected Because of this importance, germ cells have developed specialized quality control systems that consist of specific checkpoints that monitor the integrity of the DNA as well as the correct alignment of homologous chromosomes during meiosis. We review the molecular mechanisms, with a focus on the DNA damage checkpoint, show its evolutionary conservation and discuss the potential for fertility-saving therapies
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