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The Multifunctional Sorting Protein PACS-2 Regulates SIRT1-Mediated Deacetylation of p53 to Modulate p21-Dependent Cell-Cycle Arrest

Atkins, KM and Thomas, LL and Barroso-Gonzalez, J and Thomas, L and Auclair, S and Yin, J and Kang, H and Chung, JH and Dikeakos, JD and Thomas, G (2014) The Multifunctional Sorting Protein PACS-2 Regulates SIRT1-Mediated Deacetylation of p53 to Modulate p21-Dependent Cell-Cycle Arrest. Cell Reports, 8 (5). 1545 - 1557.

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Abstract

© 2014 The Authors. SIRT1 regulates the DNA damage response by deacetylating p53, thereby repressing p53 transcriptional output. Here, we demonstrate that the sortingprotein PACS-2 regulates SIRT1-mediated deacetylation of p53 to modulate the DNA damage response. PACS-2 knockdown cells failed to efficiently undergo p53-induced cell-cycle arrest in response to DNA damage. Accordingly, p53 acetylation was reduced both in PACS-2 knockdown cells and thymocytes from Pacs-2-/- mice, thereby blunting induction of the cyclin-dependent kinase inhibitor p21 (CDKN1A). The SIRT1 inhibitor EX-527 or SIRT1 knockdown restored p53 acetylation and p21 induction as well as p21-dependent cell-cycle arrest in PACS-2 knockdown cells. Traffickingstudies revealed that cytoplasmic PACS-2 shuttled to the nucleus, where it interacted with SIRT1 andrepressed SIRT1-mediated p53 deacetylation. Correspondingly, invitro assays demonstrated that PACS-2 directly inhibited SIRT1-catalyzed p53 deacetylation. Together, these findings identify PACS-2 as an invivo mediator of the SIRT1-p53-p21 axis that modulates the DNA damage response.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Atkins, KM
Thomas, LL
Barroso-Gonzalez, J
Thomas, LTHOMASLA@pitt.eduTHOMASLA
Auclair, S
Yin, J
Kang, H
Chung, JH
Dikeakos, JD
Thomas, Gthomasg@pitt.eduTHOMASG
Date: 1 January 2014
Date Type: Publication
Journal or Publication Title: Cell Reports
Volume: 8
Number: 5
Page Range: 1545 - 1557
DOI or Unique Handle: 10.1016/j.celrep.2014.07.049
Schools and Programs: School of Medicine > Microbiology and Molecular Genetics
Refereed: Yes
Date Deposited: 22 May 2015 21:49
Last Modified: 16 Feb 2019 22:55
URI: http://d-scholarship.pitt.edu/id/eprint/24729

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