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@article{Fletcher:2022:10.1186/s12943-022-01540-w,
author = {Fletcher, C and Deng, L and Orafidiya, F and Yuan, W and Lorentzen, M and Cyran, O and Varela, Carver A and Constantin, T and Dobbs, F and Figueiredo, I and Gurel, B and Parkes, E and Bogdan, D and Pereira, R and Zhao, S and Neeb, A and Issa, F and Hester, J and Kudo, H and Liu, Y and Philippou, Y and Bristow, R and Knudsen, K and Bryant, R and Feng, F and Reed, S and Mills, I and de, Bono J and Bevan, C},
doi = {10.1186/s12943-022-01540-w},
journal = {Molecular Cancer},
title = {A non-coding RNA balancing act: miR-346-induced DNA damage is limited by the long non-coding RNA NORAD in prostate cancer},
url = {http://dx.doi.org/10.1186/s12943-022-01540-w},
volume = {21},
year = {2022}
}

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TY  - JOUR
AB  - Background: miR346 was identified as an activator of Androgen Receptor (AR) signalling that associates with DNA damage response (DDR)linked transcripts in prostate cancer (PC). We sought to delineate the impact of miR346 on DNA damage, and its potential as a therapeutic agent.Methods: RNAIP, RNAseq, RNAISH, DNA fibre assays, in vivo xenograft studies and bioinformatics approaches were used alongside a novel method for amplificationfree, single nucleotideresolution genomewide mapping of DNA breaks (INDUCEseq).Results: miR346 induces rapid and extensive DNA damage in PC cells  the first report of microRNAinduced DNA damage. Mechanistically, this is achieved through transcriptional hyperactivation, Rloop formation and replication stress, leading to checkpoint activation and cell cycle arrest. miR346 also interacts with genomeprotective lncRNA NORAD to disrupt its interaction with PUM2, leading to PUM2 stabilisation and its increased turnover of DNA damage response (DDR) transcripts. Confirming clinical relevance, NORAD expression and activity strongly correlate with poorPC clinical outcomes and increased DDR in biopsy RNAseq studies. In contrast, miR346 is associated with improved PC survival.INDUCEseq reveals that miR346induced DSBs occur preferentially at binding sites of the most highlytranscriptionally active transcription factors in PC cells, including cMyc, FOXA1, HOXB13, NKX3.1, and importantly, AR, resulting in target transcript downregulation. Further, RNAseq reveals widespread miR346 and shNORAD dysregulation of DNAdamage, replication and cell cycle processes.NORAD drives targetdirected miR decay (TDMD) of miR346 as a novel genome protection mechanism: NORAD silencing increases mature miR346 levels by several thousandfold, and WT but not TDMDmutant NORAD rescues miR346induced DNA damage. Importantly, miR346 sensitises PC cells to DNAdamaging drugs including PARP inhibitor and chemotherapy, and induces tumour regression as a m
AU  - Fletcher,C
AU  - Deng,L
AU  - Orafidiya,F
AU  - Yuan,W
AU  - Lorentzen,M
AU  - Cyran,O
AU  - Varela,Carver A
AU  - Constantin,T
AU  - Dobbs,F
AU  - Figueiredo,I
AU  - Gurel,B
AU  - Parkes,E
AU  - Bogdan,D
AU  - Pereira,R
AU  - Zhao,S
AU  - Neeb,A
AU  - Issa,F
AU  - Hester,J
AU  - Kudo,H
AU  - Liu,Y
AU  - Philippou,Y
AU  - Bristow,R
AU  - Knudsen,K
AU  - Bryant,R
AU  - Feng,F
AU  - Reed,S
AU  - Mills,I
AU  - de,Bono J
AU  - Bevan,C
DO  - 10.1186/s12943-022-01540-w
PY  - 2022///
SN  - 1476-4598
TI  - A non-coding RNA balancing act: miR-346-induced DNA damage is limited by the long non-coding RNA NORAD in prostate cancer
T2  - Molecular Cancer
UR  - http://dx.doi.org/10.1186/s12943-022-01540-w
UR  - https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-022-01540-w
UR  - http://hdl.handle.net/10044/1/95759
VL  - 21
ER  -

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