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p53 coordinates DNA repair with nucleotide synthesis by suppressing PFKFB3 expression and promoting the pentose

Derek A Franklin1,2, Yizhou He1,3, Patrick L Leslie1,3

  • 1Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Scientific Reports
|December 1, 2016
PubMed

Insights

The tumor suppressor p53 aids DNA repair by repressing PFKFB3, boosting nucleotide synthesis. This metabolic shift enhances DNA repair and cell survival, revealing a key link between p53, metabolism, and DNA damage response.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Metabolic Regulation

Background:

  • p53 activation is crucial for tumor suppression via cell cycle arrest and apoptosis.
  • Emerging evidence highlights p53's roles in DNA damage repair (DDR) and metabolism.
  • The interplay between p53-mediated DDR and metabolic regulation is not fully understood.

Purpose of the Study:

  • To investigate the mechanistic connection between p53-regulated metabolism and DNA damage repair.
  • To identify novel p53 targets involved in this interplay.

Main Methods:

  • Analysis of p53's regulation of metabolic enzymes in response to DNA damage.
  • Assessing the impact of PFKFB3 suppression on glucose flux, nucleotide biosynthesis, and DDR.
  • Evaluating the roles of NADPH and nucleotides in p53-mediated DDR.

Main Results:

  • p53 represses the expression of phosphofructokinase-2 (PFKFB3), a key glycolytic enzyme.
  • PFKFB3 suppression redirects glucose towards the pentose phosphate pathway (PPP), enhancing nucleotide production.
  • Increased nucleotide synthesis, not NADPH, is essential for p53-mediated DNA damage repair and cell survival.

Conclusions:

  • p53 regulates nucleotide biosynthesis via PFKFB3 repression, linking metabolism to DNA repair.
  • This novel mechanism highlights the importance of metabolic regulation in p53-dependent tumor suppression.
  • Targeting this pathway could offer new strategies for cancer therapy.

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