RT Journal
A1 Krell, Jonathan
A1 Stebbing, Justin
A1 Carissimi, Claudia
A1 Dabrowska, Aleksandra F.
A1 de Giorgio, Alexander
A1 Frampton, Adam E.
A1 Harding, Victoria
A1 Fulci, Valerio
A1 Macino, Giuseppe
A1 Colombo, Teresa
A1 Castellano, Leandro
T1 TP53 regulates miRNA association with AGO2 to remodel the miRNA–mRNA interaction network
JF Genome Research 
JO Genome Research 
YR 2016 
FD March 01 
VO 26 
IS 3 
SP 331 
OP 341 
DO 10.1101/gr.191759.115 
UL http://genome.cshlp.org/content/26/3/331.abstract 
AB 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.