Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:5.99.1.2 (
topoisomerase
)
9,166
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The human genome contains thousands of long non-coding RNAs
1
, but specific biological functions and biochemical mechanisms have been discovered for only about a dozen
2-7
. A specific long non-coding RNA-non-coding RNA activated by DNA damage (NORAD)-has recently been shown to be required for maintaining genomic stability
8
, 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 replication-fork velocity and altered cell-cycle progression-which represent phenotypes that are mechanistically linked to TOP1 and PRPF19-CDC5L function. Expression of NORAD in trans can rescue defects caused by NORAD depletion, but rescue is significantly impaired when the
RBMX
-binding site in NORAD is deleted. Our results demonstrate that the interaction between NORAD and
RBMX
is important for NORAD function, and that NORAD is required for the assembly of the previously unknown
topoisomerase
complex NARC1, which contributes to maintaining genomic stability. In addition, we uncover a previously unknown function for long non-coding RNAs in modulating the ability of an RNA-binding protein to assemble a higher-order ribonucleoprotein complex.
...
PMID:The NORAD lncRNA assembles a topoisomerase complex critical for genome stability. 3027 76
