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Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
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The multifunctional sorting protein PACS-2 regulates SIRT1-mediated deacetylation of p53 to modulate p21-dependent

Katelyn M Atkins1, Laura L Thomas2, Jonathan Barroso-González2

  • 1Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, OR 97239, USA.

Cell Reports
|August 28, 2014
PubMed

Insights

The sorting protein PACS-2 regulates the DNA damage response by controlling SIRT1

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • SIRT1 deacetylates p53, repressing its transcriptional activity during DNA damage.
  • The role of protein trafficking in DNA damage response regulation is emerging.

Purpose of the Study:

  • To investigate the role of sorting protein PACS-2 in the DNA damage response.
  • To elucidate the mechanism by which PACS-2 modulates SIRT1-mediated p53 regulation.

Main Methods:

  • PACS-2 knockdown and knockout models (Pacs-2(-/-) mice).
  • Analysis of p53 acetylation and p21 (CDKN1A) induction.
  • Cell-cycle arrest assays.
  • SIRT1 inhibition (EX-527) and knockdown.
  • Subcellular localization studies (trafficking).
  • In vitro deacetylation assays.

Main Results:

  • PACS-2 knockdown impaired p53-induced cell-cycle arrest and p21 induction.
  • Reduced p53 acetylation was observed in PACS-2 deficient cells and mice.
  • SIRT1 inhibition or knockdown rescued p53 acetylation and p21 induction in PACS-2 knockdown cells.
  • PACS-2 shuttles to the nucleus and directly inhibits SIRT1-mediated p53 deacetylation.

Conclusions:

  • PACS-2 is a novel regulator of the SIRT1-p53-p21 pathway.
  • PACS-2 modulates the DNA damage response by controlling p53 acetylation.
  • PACS-2 acts as an in vivo mediator in the DNA damage response pathway.

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