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Deacetylation Assays to Unravel the Interplay between Sirtuins (SIRT2) and Specific Protein-substrates
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Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity

Eun-Joo Kim1, Jeong-Hoon Kho, Moo-Rim Kang

  • 1Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-dong, Kwangjin-gu, Seoul 143-747, Korea. ejk93@hanmail.net

Molecular Cell
|October 30, 2007
PubMed

Insights

Active regulator of SIRT1 (AROS) directly controls SIRT1 deacetylase activity, impacting p53 regulation. This discovery reveals AROS as the first identified SIRT1 regulator, influencing cell survival and growth.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • SIRT1 is a crucial NAD+-dependent deacetylase involved in cell death, survival, senescence, and endocrine signaling.
  • While SIRT1 substrates like p53 are known, its direct regulators remain unidentified.

Purpose of the Study:

  • To identify and characterize direct regulators of human SIRT1.
  • To elucidate the role of AROS in modulating SIRT1 activity and p53 function.

Main Methods:

  • In vitro and in vivo assays to assess AROS's effect on SIRT1-mediated p53 deacetylation.
  • Utilized SIRT1 inhibitors (splitomicin, nicotinamide) and small interfering RNA (siRNA) to probe AROS-SIRT1 interactions.
  • Investigated AROS binding-defective SIRT1 mutants.
  • Employed antisense expression vectors for AROS knockdown and assessed effects on p21WAF1 expression, cell cycle, and apoptosis.

Main Results:

  • AROS directly enhances SIRT1-mediated deacetylation of p53.
  • AROS inhibits p53-mediated transcriptional activity.
  • AROS's function is dependent on active SIRT1, as shown by abrogation with inhibitors and siRNA, and failure to cooperate with a binding-defective SIRT1 mutant.
  • Knockdown of AROS increases p21WAF1 expression and DNA damage-induced apoptosis, while AROS overexpression promotes cell survival.

Conclusions:

  • AROS is identified as the first direct regulator of SIRT1.
  • AROS modulates p53 activity, thereby influencing p53-mediated growth regulation.
  • AROS plays a significant role in cell survival and response to DNA damage.

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