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TP53 regulates miRNA association with AGO2 to remodel the miRNA–mRNA interaction network

DNA damage activates TP53-regulated surveillance mechanisms that are crucial in suppressing tumorigenesis. TP53 orchestrates these responses directly by transcriptionally modulating genes, including microRNAs (miRNAs), and by regulating miRNA biogenesis through interacting with the DROSHA complex. H...

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Autores principales: Krell, Jonathan, Stebbing, Justin, Carissimi, Claudia, Dabrowska, Aleksandra F., de Giorgio, Alexander, Frampton, Adam E., Harding, Victoria, Fulci, Valerio, Macino, Giuseppe, Colombo, Teresa, Castellano, Leandro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772015/
https://www.ncbi.nlm.nih.gov/pubmed/26701625
http://dx.doi.org/10.1101/gr.191759.115
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author Krell, Jonathan
Stebbing, Justin
Carissimi, Claudia
Dabrowska, Aleksandra F.
de Giorgio, Alexander
Frampton, Adam E.
Harding, Victoria
Fulci, Valerio
Macino, Giuseppe
Colombo, Teresa
Castellano, Leandro
author_facet Krell, Jonathan
Stebbing, Justin
Carissimi, Claudia
Dabrowska, Aleksandra F.
de Giorgio, Alexander
Frampton, Adam E.
Harding, Victoria
Fulci, Valerio
Macino, Giuseppe
Colombo, Teresa
Castellano, Leandro
author_sort Krell, Jonathan
collection PubMed
description DNA damage activates TP53-regulated surveillance mechanisms that are crucial in suppressing tumorigenesis. TP53 orchestrates these responses directly by transcriptionally modulating genes, including microRNAs (miRNAs), and by regulating miRNA biogenesis through interacting with the DROSHA complex. However, whether the association between miRNAs and AGO2 is regulated following DNA damage is not yet known. Here, we show that, following DNA damage, TP53 interacts with AGO2 to induce or reduce AGO2's association of a subset of miRNAs, including multiple let-7 family members. Furthermore, we show that specific mutations in TP53 decrease rather than increase the association of let-7 family miRNAs, reducing their activity without preventing TP53 from interacting with AGO2. This is consistent with the oncogenic properties of these mutants. Using AGO2 RIP-seq and PAR-CLIP-seq, we show that the DNA damage–induced increase in binding of let-7 family members to the RISC complex is functional. We unambiguously determine the global miRNA–mRNA interaction networks involved in the DNA damage response, validating them through the identification of miRNA-target chimeras formed by endogenous ligation reactions. We find that the target complementary region of the let-7 seed tends to have highly fixed positions and more variable ones. Additionally, we observe that miRNAs, whose cellular abundance or differential association with AGO2 is regulated by TP53, are involved in an intricate network of regulatory feedback and feedforward circuits. TP53-mediated regulation of AGO2–miRNA interaction represents a new mechanism of miRNA regulation in carcinogenesis.
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spelling pubmed-47720152016-03-15 TP53 regulates miRNA association with AGO2 to remodel the miRNA–mRNA interaction network Krell, Jonathan Stebbing, Justin Carissimi, Claudia Dabrowska, Aleksandra F. de Giorgio, Alexander Frampton, Adam E. Harding, Victoria Fulci, Valerio Macino, Giuseppe Colombo, Teresa Castellano, Leandro Genome Res Research DNA damage activates TP53-regulated surveillance mechanisms that are crucial in suppressing tumorigenesis. TP53 orchestrates these responses directly by transcriptionally modulating genes, including microRNAs (miRNAs), and by regulating miRNA biogenesis through interacting with the DROSHA complex. However, whether the association between miRNAs and AGO2 is regulated following DNA damage is not yet known. Here, we show that, following DNA damage, TP53 interacts with AGO2 to induce or reduce AGO2's association of a subset of miRNAs, including multiple let-7 family members. Furthermore, we show that specific mutations in TP53 decrease rather than increase the association of let-7 family miRNAs, reducing their activity without preventing TP53 from interacting with AGO2. This is consistent with the oncogenic properties of these mutants. Using AGO2 RIP-seq and PAR-CLIP-seq, we show that the DNA damage–induced increase in binding of let-7 family members to the RISC complex is functional. We unambiguously determine the global miRNA–mRNA interaction networks involved in the DNA damage response, validating them through the identification of miRNA-target chimeras formed by endogenous ligation reactions. We find that the target complementary region of the let-7 seed tends to have highly fixed positions and more variable ones. Additionally, we observe that miRNAs, whose cellular abundance or differential association with AGO2 is regulated by TP53, are involved in an intricate network of regulatory feedback and feedforward circuits. TP53-mediated regulation of AGO2–miRNA interaction represents a new mechanism of miRNA regulation in carcinogenesis. Cold Spring Harbor Laboratory Press 2016-03 /pmc/articles/PMC4772015/ /pubmed/26701625 http://dx.doi.org/10.1101/gr.191759.115 Text en © 2016 Krell et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research
Krell, Jonathan
Stebbing, Justin
Carissimi, Claudia
Dabrowska, Aleksandra F.
de Giorgio, Alexander
Frampton, Adam E.
Harding, Victoria
Fulci, Valerio
Macino, Giuseppe
Colombo, Teresa
Castellano, Leandro
TP53 regulates miRNA association with AGO2 to remodel the miRNA–mRNA interaction network
title TP53 regulates miRNA association with AGO2 to remodel the miRNA–mRNA interaction network
title_full TP53 regulates miRNA association with AGO2 to remodel the miRNA–mRNA interaction network
title_fullStr TP53 regulates miRNA association with AGO2 to remodel the miRNA–mRNA interaction network
title_full_unstemmed TP53 regulates miRNA association with AGO2 to remodel the miRNA–mRNA interaction network
title_short TP53 regulates miRNA association with AGO2 to remodel the miRNA–mRNA interaction network
title_sort tp53 regulates mirna association with ago2 to remodel the mirna–mrna interaction network
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772015/
https://www.ncbi.nlm.nih.gov/pubmed/26701625
http://dx.doi.org/10.1101/gr.191759.115
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