Imperial College London
Portrait Picture

DrLeandroCastellano

Faculty of Medicine, Department of Surgery & Cancer

Visiting Reader
 
 
 
//

Contact

 

+44 (0)20 7594 2822l.castellano Website

 
 
//

Location

 

ICTEM buildingHammersmith Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Krell:2015:10.1101/gr.191759.115.,
author = {Krell, J and Stebbing, J and Carissimi, C and Dabrowska, AF and de, Giorgio A and Frampton, AE and Harding, V and Fulci, V and Macino, G and Colombo, T and Castellano, L},
doi = {10.1101/gr.191759.115.},
journal = {Genome Research},
title = {TP53 regulates miRNA association with AGO2 to remodel the miRNA-mRNA interaction network.},
url = {http://dx.doi.org/10.1101/gr.191759.115.},
year = {2015}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
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.
AU  - Krell,J
AU  - Stebbing,J
AU  - Carissimi,C
AU  - Dabrowska,AF
AU  - de,Giorgio A
AU  - Frampton,AE
AU  - Harding,V
AU  - Fulci,V
AU  - Macino,G
AU  - Colombo,T
AU  - Castellano,L
DO  - 10.1101/gr.191759.115.
PY  - 2015///
SN  - 1549-5469
TI  - TP53 regulates miRNA association with AGO2 to remodel the miRNA-mRNA interaction network.
T2  - Genome Research
UR  - http://dx.doi.org/10.1101/gr.191759.115.
UR  - http://hdl.handle.net/10044/1/30899
ER  -
Download