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TSPYL2 is a novel regulator of SIRT1 and p300 activity in response to DNA damage.
- Source :
-
Cell death and differentiation [Cell Death Differ] 2019 May; Vol. 26 (5), pp. 918-931. Date of Electronic Publication: 2018 Jul 26. - Publication Year :
- 2019
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Abstract
- Protein acetylation and deacetylation events are finely regulated by lysine-acetyl-transferases and lysine-deacetylases and constitute an important tool for the activation or inhibition of specific cellular pathways. One of the most important lysine-acetyl-transferases is p300, which is involved in the regulation of gene expression, cell growth, DNA repair, differentiation, apoptosis, and tumorigenesis. A well-known target of p300 is constituted by the tumor suppressor protein p53, which plays a critical role in the maintenance of genomic stability and whose activity is known to be controlled by post-translational modifications, among which acetylation. p300 activity toward p53 is negatively regulated by the NAD-dependent deacetylase SIRT1, which deacetylates p53 preventing its transcriptional activation and the induction of p53-dependent apoptosis. However, the mechanisms responsible for p53 regulation by p300 and SIRT1 are still poorly understood. Here we identify the nucleosome assembly protein TSPY-Like 2 (TSPYL2, also known as TSPX, DENTT, and CDA1) as a novel regulator of SIRT1 and p300 function. We demonstrate that, upon DNA damage, TSPYL2 inhibits SIRT1, disrupting its association with target proteins, and promotes p300 acetylation and activation, finally stimulating p53 acetylation and p53-dependent cell death. Indeed, in response to DNA damage, cells silenced for TSPYL2 were found to be defective in p53 activation and apoptosis induction and these events were shown to be dependent on SIRT1 and p300 function. Collectively, our results shed new light on the regulation of p53 acetylation and activation and reveal a novel TSPYL2 function with important implications in cancerogenesis.
- Subjects :
- A549 Cells
Acetylation drug effects
Apoptosis drug effects
Camptothecin pharmacology
Cell Proliferation drug effects
Chromatin Assembly and Disassembly genetics
DNA Damage drug effects
DNA-Binding Proteins
Deoxycytidine analogs & derivatives
Deoxycytidine pharmacology
Etoposide pharmacology
Gene Expression Regulation, Neoplastic drug effects
Humans
Lung Neoplasms drug therapy
Lung Neoplasms pathology
Protein Processing, Post-Translational genetics
Transcriptional Activation drug effects
Gemcitabine
E1A-Associated p300 Protein genetics
Lung Neoplasms genetics
Nuclear Proteins genetics
Sirtuin 1 genetics
Tumor Suppressor Protein p53 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5403
- Volume :
- 26
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cell death and differentiation
- Publication Type :
- Academic Journal
- Accession number :
- 30050056
- Full Text :
- https://doi.org/10.1038/s41418-018-0168-6