The lnCRNA NORAD Contributes to the Maintenance of Genomic Stability

Only a fraction of the long noncoding RNAs (lncRNA) in the genome have been functionally characterized. NORAD is a highly conserved lncRNA expressed at high levels in many cell types. It is upregulated upon DNA damage, and its loss promotes chromosomal instability and aneuploidy. However, the mechanism by which NORAD regulates chromosomal instability has not been determined. To identify proteins that directly interact with NORAD, Munschauer and colleagues performed RNA antisense purification (RAP) combined with quantitative liquid chromatography/mass spectrometry using mass tag quantification (RAP MS). This approach revealed that NORAD binds to a number of nuclear proteins in colon cancer cells including RBMX. Knockdown of RBMX resulted in impaired DNA damage repair and premature sister-chromatid separation, similar to the NORAD depletion. NORAD contains the strongest RBMX-binding site in the transcriptome, and RNA immunoprecipitation confirmed that NORAD and RBMX interact in the nucleus of cells. NORAD was required for RBMX to assemble a ribonucleoprotein complex, termed NORAD-activated ribonucleoprotein complex I (NARC1), which contains known suppressors of genomic instability including topoisomerase I, ALYREF, and the PRPF19–CDC5L complex. Depleting NORAD or RBMX promoted chromosome segregation defects, reduced replication fork speed, and disrupted cell-cycle progression, effects that could be rescued by wild-type NORAD expression. However, NORAD could not restore genome stability when the RBMX binding domain was deleted, indicating that the interaction with RBMX is required for NORAD function. Altogether, these findings indicate that DNA damage–mediated induction of NORAD can promote the assembly of the NARC1 complex in the nucleus to promote genome stability.

Munschauer M, Nguyen CT, Sirokman K, Hartigan CR, Hogstrom L, Engreitz JM, et al. The NORAD lncRNA assembles a topoisomerase complex critical for genome stability. Nature 2018;561:132–6.

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