DNA damage-induced primordial follicle oocyte apoptosis and loss of fertility require TAp63-mediated induction of Puma and Noxa

Mol Cell. 2012 Nov 9;48(3):343-52. doi: 10.1016/j.molcel.2012.08.017. Epub 2012 Sep 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Apoptosis / radiation effects
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / metabolism
  • DNA Damage*
  • Female
  • Fertility / genetics*
  • Gamma Rays
  • Gene Expression / radiation effects
  • Immunohistochemistry
  • In Situ Hybridization
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oocytes / cytology
  • Oocytes / metabolism*
  • Oocytes / radiation effects
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • PUMA protein, mouse
  • Phosphoproteins
  • Pmaip1 protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • Trans-Activators
  • Trp63 protein, mouse
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins