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HDAC5, a key component in temporal regulation of p53-mediated transactivation in response to genotoxic stress

Nirmalya Sen1, Rajni Kumari, Manika Indrajit Singh

  • 1Molecular Oncology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.

Molecular Cell
|October 15, 2013
PubMed

Insights

Histone deacetylase 5 (HDAC5) regulates p53

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • The temporal regulation of p53-mediated transcription is not fully understood.
  • Posttranslational modifications, such as K120 acetylation, are crucial for p53 target specificity.
  • K120 acetylation is essential for recruiting p53 to proapoptotic genes.

Purpose of the Study:

  • To investigate the role of histone deacetylase 5 (HDAC5) in regulating p53-mediated transcription.
  • To elucidate the mechanism by which HDAC5 influences p53 target gene selection and cell fate decisions.

Main Methods:

  • Co-immunoprecipitation assays to detect p53-HDAC5 binding.
  • Western blotting to assess K120 acetylation levels of p53.
  • Analysis of p53 recruitment to target gene promoters.
  • Studies in a mouse model with downregulated HDAC5 expression.

Main Results:

  • HDAC5 binds to p53 and inhibits K120 acetylation, promoting p53 recruitment to proarrest and antioxidant genes early in stress response.
  • HDAC5 nuclear export upon prolonged genotoxic stress leads to K120 acetylation and p53-mediated apoptosis.
  • Downregulation of HDAC5 accelerates apoptosis in mice under genotoxic stress.

Conclusions:

  • HDAC5 acts as a critical regulator of p53-mediated cell fate decisions.
  • HDAC5's dynamic localization and activity determine the balance between cell cycle arrest and apoptosis.
  • HDAC5 is a key determinant of cellular response to genotoxic stress.

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