The role of TP53 in miRNA loading onto AGO2 and in remodelling the miRNA–mRNA interaction network

摘要: Abstract Background DNA damage transactivates tumour protein p53 (TP53) -regulated surveillance, crucial in suppressing tumorigenesis. TP53 mediates this process directly by transcriptionally modulating gene and microRNA (miRNA) expression indirectly regulating miRNA biogenesis. However, the role of miRNA-AGO2 loading global changes AGO2 binding to its targets response are unknown. These processes might be novel mechanisms which regulates miRNAs damage. Methods To show network miRNA–mRNA interactions that occur damage, we stimulated wild-type null cell-lines with doxorubicin performed RNA sequencing from total (RNA-Seq) AGO2-immunoprecipitated (AGO2-RIP-Seq). We used a combined RIP-seq PAR-CLIP-seq (photoactivatable-ribonucleoside-enhanced cross-linking immunoprecipitation) approach determine exact sites interaction between AGO2-bound their mRNA targets. Findings associated AGO2, induced reduced subset miRNAs, including lethal 7 (let-7) family members, onto Although mutated maintained capacity interact it mediated unloading instead let-7 thereby reducing activity. determined networks involved both presence absence . Furthermore, showed whose cellular abundance or differential was regulated were an intricate regulatory feedback feedforward circuits fine-tuned levels permit repair initiation programmed cell death. Interpretation Control is new mechanism regulation carcinogenesis. Funding UK Medical Research Council, Action Against Cancer.