DNA Damage-Induced Primordial Follicle Oocyte Apoptosis and Loss of Fertility Require TAp63-Mediated Induction of Puma and Noxa

Abstract

SUMMARY Trp63, a transcription factor related to the tumor suppressor p53, is activated by diverse stimuli and can initiate a range of cellular responses. TAp63 is the predominant Trp53 family member in primordial follicle oocytes and essential for their apoptosis triggered by DNA damage in vivo. Following γ-irradiation, induction of the pro-apoptotic BH3-only members Puma and Noxa was observed in primordial follicle oocytes from wt and Trp53−/− mice but not in those from TAp63 deficient mice. Primordial follicle oocytes from mice lacking Puma or both Puma and Noxa were protected from γ-irradiation-induced apoptosis and, remarkably, could produce healthy offspring. Hence, PUMA and NOXA are critical for DNA damage-induced, TAp63-mediated primordial follicle oocyte apoptosis. Thus, blockade of PUMA may protect fertility during cancer therapy and prevent premature menopause, improving women’s health.

DNA damage response during mouse oocyte maturation

“…9 Ionizing irradiation causes loss of primordial follicles through TAp63-dependent expression of proapoptotic proteins PUMA and NOXA in oocytes. Interestingly, the fertility of Puma ¡/¡ Noxa ¡/¡ mice exposed to ionizing radiation is the same as wild type non-irradiated controls, 10 which suggests that oocytes can repair DSBs during the long prophase I arrest. 11 Mouse oocytes from preovulatory follicles can detect DSBs as documented by gH2AX foci formation after exogenous DSBs induction.…”

Analysis of the oligomeric state and transactivation potential of TAp73α

“…11 Detection of DNA damage leads to the activation of p63, which results in the elimination of these compromised oocytes. 12 The high expression level of p63 in resting, non compromised oocytes suggested that its transcriptional activity must be inhibited, and only becomes activated upon the detection of DNA damage. In a recent study we had started to investigate the mechanism that keeps p63 inactive.…”

The DNA Damage Response in Mammalian Oocytes.

“…It would be expected that these oocytes carry significant damage that could be transferred to their offspring. However, an exciting result refutes these concerns: although wild type mice lose their primordial follicle reserve and become infertile following genotoxic stress, PUMA −/− and PUMA −/− NOXA −/− female mice exposed to ionizing radiation have viable, healthy, and fertile offspring at the same rate as wild type mice not exposed to DNA damage (Kerr et al, 2012c). This finding suggests that during their long prophase arrest, oocytes possess the ability to repair DNA damage efficiently.…”

“…TAp63 enables the transcription of both PUMA and NOXA in mouse primordial follicle oocytes. In addition, PUMA −/− mice and especially the double mutants PUMA −/− NOXA −/− mice, do not lose their primordial follicle pool in response to genotoxic stress (Kerr et al, 2012c). Therefore, TAp63-dependent PUMA and…”

“…Recently, two such targets have been identified in mouse oocytes, namely PUMA and NOXA (Kerr et al, 2012c). Both proteins belong to the pro-apoptotic arm of the Bcl-2 family and they have been known to inhibit pro-survival Bcl-2 proteins and promote the function of BAX and BAK, two major pro-apoptotic Bcl-2 family members, which in turn enable the mitochondria-induced apoptosis mechanisms (Chipuk and Green, 2008;Youle and Strasser, 2008).…”