The NORAD lncRNA assembles a topoisomerase complex critical for genome stability

Nature
Mathias MunschauerEric S Lander

Abstract

The human genome contains thousands of long non-coding RNAs1, but specific biological functions and biochemical mechanisms have been discovered for only about a dozen2-7. A specific long non-coding RNA-non-coding RNA activated by DNA damage (NORAD)-has recently been shown to be required for maintaining genomic stability8, but its molecular mechanism is unknown. Here we combine RNA antisense purification and quantitative mass spectrometry to identify proteins that directly interact with NORAD in living cells. We show that NORAD interacts with proteins involved in DNA replication and repair in steady-state cells and localizes to the nucleus upon stimulation with replication stress or DNA damage. In particular, NORAD interacts with RBMX, a component of the DNA-damage response, and contains the strongest RBMX-binding site in the transcriptome. We demonstrate that NORAD controls the ability of RBMX to assemble a ribonucleoprotein complex-which we term NORAD-activated ribonucleoprotein complex 1 (NARC1)-that contains the known suppressors of genomic instability topoisomerase I (TOP1), ALYREF and the PRPF19-CDC5L complex. Cells depleted for NORAD or RBMX display an increased frequency of chromosome segregation defects, reduced replica...Continue Reading

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Citations

Feb 14, 2019·PLoS Biology·Emily DangelmaierAshish Lal
Feb 9, 2019·ELife·Florian KoppJoshua T Mendell
Mar 20, 2019·Journal of Cellular Physiology·Jinglin LiYunfu Cui
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Datasets Mentioned

BETA
GSE114953

Methods Mentioned

BETA
antisense purification
antisense oligonucleotides
RAP
antisense purifications
PCR
immunoprecipitation
CLIP
co-immunoprecipitation
co-IP
size-exclusion chromatography

Software Mentioned

Spectrum
MACS2
MarkDuplicates
TopHat
Stringtie
diffSplice
STAR
MATLAB
R
Cell Profiler

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