Noncoding RNA NORAD regulates genomic stability by sequestering PUMILIO proteins

By Sungyul Lee, F. Kopp, Tsung-Cheng Chang, Anupama Sataluri, Beibei Chen, Sushama Sivakumar, Hongtao Yu, Yang Xie, Joshua T. Mendell. Cell, 2015

807 citations recorded by the source corpus.

SUMMARY Long noncoding RNAs (lncRNAs) have emerged as regulators of diverse biological processes. Here we describe the initial functional analysis of a poorly characterized human lncRNA (LINC00657) that is induced after DNA damage, which we termed Noncoding RNA Activated by DNA Damage or NORAD. NORAD is highly conserved and abundant, with expression levels of approximately 500–1,000 copies per cell. Remarkably, inactivation of NORAD triggers dramatic aneuploidy in previously karyotypically-stable cell lines. NORAD maintains genomic stability by sequestering PUMILIO proteins, which repress the stability and translation of messenger RNAs to which they bind. In the absence of NORAD, PUMILIO proteins drive chromosomal instability by hyperactively repressing mitotic, DNA repair, and DNA replication factors. These findings introduce a mechanism that regulates the activity of a deeply conserved and highly dosage-sensitive family of RNA binding proteins and reveal unanticipated roles for a lncRNA and PUMILIO proteins in the maintenance of genomic stability.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/20e6901b10466764b6c2a7b73e8731d1ff9877f0

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In Cancer Research

1. J. J. Chan
2. Yvonne Tay
3. Ling-Ling Chen

In Molecular Biology

1. Yvonne Tay
2. J. J. Chan
3. Amanda C. Daulagala
4. M. Bridges
5. A. Kourtidis
6. Ling-Ling Chen

Citations in the corpus

• Noncoding RNA:RNA Regulatory Networks in Cancer (2018, background): “3 kb lncRNA which is broadly and abundantly expressed in human tissues and cell lines [73].”
• Linking Long Noncoding RNA Localization and Function. (2016, background): “Furthermore, cytoplasmic lncRNAs can influence gene regulation by acting as decoys for miRNAs [40] and proteins [41].”
• LNCcation: lncRNA localization and function (2021, background): “Antisense oligonucleotides have proven to be more effective in targeting nuclearlocalized lncRNAs, whereas RNAi-based methodologies are more appropriate to target cytoplasmic ones (Lennox and Behlke, 2016).”
• The stress granule transcriptome reveals principles of mRNA accumulation in stress granules (2017, neutral): “NORAD is one of the top 10 most enriched lincRNAs in SGs (Table S3A) and is thought to function as a Pumulio sponge (Lee et al., 2016; Tichon et al., 2016).”
• RNA-Binding Proteins in Cancer: Old Players and New Actors. (2017, background): “Recently, the lncRNA NORAD was identified as essential for maintaining chromosomal stability in mammalian cells [116,117].”