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

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 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.

Defining a microRNA-mRNA interaction map for calcineurin inhibitor induced nephrotoxicity

“…Thus, only a fraction of expressed miRNAs actively target mRNAs. This phenomenon has been observed previously in an AGO‐PAR‐CLIP study of TP53‐dependent miRNA‐AGO2 association in which most miRNAs differentially expressed in the RISC associated with AGO2 did not correspond to relative abundance in total RNA samples . While we do not know why only a relatively small number of total miRNAs are bound to AGO2, we speculate that some miRNAs may compete for binding to AGO2 better than others.…”

Human Pericardial Fluid Contains Exosomes Enriched with Cardiovascular-Expressed MicroRNAs and Promotes Therapeutic Angiogenesis

“…In fact, it is emerging that the association between miRNAs and the RISC complex is a regulated process. As an example, Krell et al 33 . showed that following DNA damage, P53 interacts with AGO-2 to induce or reduce AGO-2’s association with subsets of miRNAs, including multiple let-7 family members.…”

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

“…miRNAs are involved in most developmental and physiological processes and their deregulation is linked to many human diseases, including cancer (Siomi & Siomi 2010, Krell et al 2015. Several studies have shown that miRNAs can act as both oncogenes and tumour suppressors and expression profiling has associated specific miRNAs with a variety of cancers in the hope of developing tumour subtype-specific signatures (Calin & Croce 2006, Esquela-Kerscher & Slack 2006, Weber et al 2006, Zhang et al 2007.…”