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.
Abstract
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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Item Type: |
Article
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Status: |
Published |
Creators/Authors: |
Creators | Email | Pitt Username | ORCID |
---|
Atkins, KM | | | | Thomas, LL | | | | Barroso-Gonzalez, J | | | | Thomas, L | THOMASLA@pitt.edu | THOMASLA | | Auclair, S | | | | Yin, J | | | | Kang, H | | | | Chung, JH | | | | Dikeakos, JD | | | | Thomas, G | thomasg@pitt.edu | THOMASG | |
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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: |
22 Jun 2021 13:56 |
URI: |
http://d-scholarship.pitt.edu/id/eprint/24729 |
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