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DNA Damage Regulates the Functions of the RNA Binding Protein Sam68 through ATM-Dependent Phosphorylation
SIMPLE SUMMARY: Alterations of the complex network of interactions between the DNA damage response pathway and RNA metabolism have been described in several tumors, and increasing efforts are devoted to the elucidation of the molecular mechanisms involved in this network. Previous large-scale proteo...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9405969/ https://www.ncbi.nlm.nih.gov/pubmed/36010841 http://dx.doi.org/10.3390/cancers14163847 |
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author | Stagni, Venturina Orecchia, Silvia Mignini, Luca Beji, Sara Antonioni, Ambra Caggiano, Cinzia Barilà, Daniela Bielli, Pamela Sette, Claudio |
author_facet | Stagni, Venturina Orecchia, Silvia Mignini, Luca Beji, Sara Antonioni, Ambra Caggiano, Cinzia Barilà, Daniela Bielli, Pamela Sette, Claudio |
author_sort | Stagni, Venturina |
collection | PubMed |
description | SIMPLE SUMMARY: Alterations of the complex network of interactions between the DNA damage response pathway and RNA metabolism have been described in several tumors, and increasing efforts are devoted to the elucidation of the molecular mechanisms involved in this network. Previous large-scale proteomic studies identified the RNA binding protein Sam68 as a putative target of the ATM kinase. Herein, we demonstrate that ATM phosphorylates Sam68 upon DNA damage induction, and this post-translational modification regulates both the signaling function of Sam68 in the initial phase of the DNA damage response and its RNA processing activity. Thus, our study uncovers anew crosstalk between ATM and Sam68, which may represent a paradigm for the functional interaction between the DDR pathway and RNA binding proteins, and a possible actionabletarget in human cancers. ABSTRACT: Cancer cells frequently exhibit dysregulation of the DNA damage response (DDR), genomic instability, and altered RNA metabolism. Recent genome-wide studies have strongly suggested an interaction between the pathways involved in the cellular response to DDR and in the regulation of RNA metabolism, but the molecular mechanism(s) involved in this crosstalk are largely unknown. Herein, we found that activation of the DDR kinase ATM promotes its interaction with Sam68, leading to phosphorylation of this multifunctional RNA binding protein (RBP) on three residues: threonine 61, serine 388 and serine 390. Moreover, we demonstrate that ATM-dependent phosphorylation of threonine 61 promotes the function of Sam68 in the DDR pathway and enhances its RNA processing activity. Importantly, ATM-mediated phosphorylation of Sam68 in prostate cancer cells modulates alternative polyadenylation of transcripts that are targets of Sam68, supporting the notion that the ATM–Sam68 axis exerts a multifaceted role in the response to DNA damage. Thus, our work validates Sam68 as an ATM kinase substrate and uncovers an unexpected bidirectional interplay between ATM and Sam68, which couples the DDR pathway to modulation of RNA metabolism in response to genotoxic stress. |
format | Online Article Text |
id | pubmed-9405969 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-94059692022-08-26 DNA Damage Regulates the Functions of the RNA Binding Protein Sam68 through ATM-Dependent Phosphorylation Stagni, Venturina Orecchia, Silvia Mignini, Luca Beji, Sara Antonioni, Ambra Caggiano, Cinzia Barilà, Daniela Bielli, Pamela Sette, Claudio Cancers (Basel) Article SIMPLE SUMMARY: Alterations of the complex network of interactions between the DNA damage response pathway and RNA metabolism have been described in several tumors, and increasing efforts are devoted to the elucidation of the molecular mechanisms involved in this network. Previous large-scale proteomic studies identified the RNA binding protein Sam68 as a putative target of the ATM kinase. Herein, we demonstrate that ATM phosphorylates Sam68 upon DNA damage induction, and this post-translational modification regulates both the signaling function of Sam68 in the initial phase of the DNA damage response and its RNA processing activity. Thus, our study uncovers anew crosstalk between ATM and Sam68, which may represent a paradigm for the functional interaction between the DDR pathway and RNA binding proteins, and a possible actionabletarget in human cancers. ABSTRACT: Cancer cells frequently exhibit dysregulation of the DNA damage response (DDR), genomic instability, and altered RNA metabolism. Recent genome-wide studies have strongly suggested an interaction between the pathways involved in the cellular response to DDR and in the regulation of RNA metabolism, but the molecular mechanism(s) involved in this crosstalk are largely unknown. Herein, we found that activation of the DDR kinase ATM promotes its interaction with Sam68, leading to phosphorylation of this multifunctional RNA binding protein (RBP) on three residues: threonine 61, serine 388 and serine 390. Moreover, we demonstrate that ATM-dependent phosphorylation of threonine 61 promotes the function of Sam68 in the DDR pathway and enhances its RNA processing activity. Importantly, ATM-mediated phosphorylation of Sam68 in prostate cancer cells modulates alternative polyadenylation of transcripts that are targets of Sam68, supporting the notion that the ATM–Sam68 axis exerts a multifaceted role in the response to DNA damage. Thus, our work validates Sam68 as an ATM kinase substrate and uncovers an unexpected bidirectional interplay between ATM and Sam68, which couples the DDR pathway to modulation of RNA metabolism in response to genotoxic stress. MDPI 2022-08-09 /pmc/articles/PMC9405969/ /pubmed/36010841 http://dx.doi.org/10.3390/cancers14163847 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Stagni, Venturina Orecchia, Silvia Mignini, Luca Beji, Sara Antonioni, Ambra Caggiano, Cinzia Barilà, Daniela Bielli, Pamela Sette, Claudio DNA Damage Regulates the Functions of the RNA Binding Protein Sam68 through ATM-Dependent Phosphorylation |
title | DNA Damage Regulates the Functions of the RNA Binding Protein Sam68 through ATM-Dependent Phosphorylation |
title_full | DNA Damage Regulates the Functions of the RNA Binding Protein Sam68 through ATM-Dependent Phosphorylation |
title_fullStr | DNA Damage Regulates the Functions of the RNA Binding Protein Sam68 through ATM-Dependent Phosphorylation |
title_full_unstemmed | DNA Damage Regulates the Functions of the RNA Binding Protein Sam68 through ATM-Dependent Phosphorylation |
title_short | DNA Damage Regulates the Functions of the RNA Binding Protein Sam68 through ATM-Dependent Phosphorylation |
title_sort | dna damage regulates the functions of the rna binding protein sam68 through atm-dependent phosphorylation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9405969/ https://www.ncbi.nlm.nih.gov/pubmed/36010841 http://dx.doi.org/10.3390/cancers14163847 |
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