title: DNA damage-induced primordial follicle oocyte apoptosis and loss of fertility require TAp63-mediated induction of Puma and Noxa.
abstract: 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 oocyte nuclei and is essential for their apoptosis triggered by DNA damage in vivo. After γ-irradiation, induction of the proapoptotic 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.
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kerr
authors.forename: Karla J
authors.initials: KJ
authors.lastname: Hutt
authors.forename: Ewa M
authors.initials: EM
authors.lastname: Michalak
authors.forename: Michele
authors.initials: M
authors.lastname: Cook
authors.forename: Cassandra J
authors.initials: CJ
authors.lastname: Vandenberg
authors.forename: Seng H
authors.initials: SH
authors.lastname: Liew
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
authors.forename: Alea
authors.initials: A
authors.lastname: Mills
authors.forename: Clare L
authors.initials: CL
authors.lastname: Scott
authors.forename: Jock K
authors.initials: JK
authors.lastname: Findlay
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D005260:Female; D005298:Fertility / Q000235:genetics*; D005720:Gamma Rays; D015870:Gene Expression / Q000528:radiation effects; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009865:Oocytes / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C488588:PUMA protein, mouse; D010750:Phosphoproteins; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins