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SIRT7 activates p53 by enhancing PCAF-mediated MDM2 degradation to arrest the cell cycle

Ya-Fei Lu1, Xiao-Peng Xu1, Xiao-Peng Lu1

  • 1Guangdong Key Laboratory of Genome Instability and Human Disease, Shenzhen University International Cancer Center, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, 518055, China.

Oncogene
|May 15, 2020
PubMed

Insights

Sirtuin 7 (SIRT7) protein is crucial for p53-mediated cell cycle arrest when glucose is scarce. It deacetylates PCAF, enhancing p53 regulation and offering a potential target for cancer therapies.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Sirtuin 7 (SIRT7), an NAD+-dependent deacetylase, is involved in energy sensing.
  • The precise mechanisms of SIRT7's action, particularly in cellular stress responses, are not fully understood.

Purpose of the Study:

  • To elucidate the role of SIRT7 in p53-dependent cell-cycle arrest under glucose deprivation.
  • To investigate the molecular interactions and signaling pathways regulated by SIRT7 during metabolic stress.

Main Methods:

  • Co-immunoprecipitation assays to study protein-protein interactions.
  • Western blotting to assess protein levels and modifications (acetylation, degradation).
  • Cell-based assays to monitor cell-cycle progression and viability.

Main Results:

  • SIRT7 directly interacts with PCAF, with increased affinity during glucose deprivation.
  • SIRT7 deacetylates PCAF at K720, promoting its binding to MDM2.
  • This interaction accelerates MDM2 degradation, upregulating p21Waf1/Cip1 and inducing cell-cycle arrest.

Conclusions:

  • The SIRT7-PCAF interaction is critical for regulating p53 activity and cell-cycle progression under glucose deprivation.
  • This pathway represents a potential therapeutic target for cancer treatments exploiting tumor starvation.

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