IRUS Total

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

File Description SizeFormat 
TP53 regulates miRNA association with AGO2.pdfAccepted version1.45 MBAdobe PDFView/Open
Title: TP53 regulates miRNA association with AGO2 to remodel the miRNA-mRNA interaction network.
Authors: Krell, J
Stebbing, J
Carissimi, C
Dabrowska, AF
De Giorgio, A
Frampton, AE
Harding, V
Fulci, V
Macino, G
Colombo, T
Castellano, L
Item Type: Journal Article
Abstract: 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 AGO2s 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.
Issue Date: 23-Dec-2015
Date of Acceptance: 17-Dec-2015
URI: http://hdl.handle.net/10044/1/30899
DOI: https://dx.doi.org/10.1101/gr.191759.115.
ISSN: 1549-5469
Publisher: Cold Spring Harbor Laboratory Press
Journal / Book Title: Genome Research
Copyright Statement: This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International license), as described at http://creativecommons.org/licenses/by/4.0/.
Keywords: Bioinformatics
06 Biological Sciences
11 Medical And Health Sciences
Publication Status: Accepted
Appears in Collections:Department of Surgery and Cancer