Noncoding RNA NORAD Regulates Genomic Stability by Sequestering PUMILIO Proteins

2015-12-29 14:11:07

Nature; 24 December 2015: DOI:

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


  • NORAD is a broadly expressed, highly abundant, and conserved mammalian lncRNA

  • Inactivation of NORAD in human cells triggers dramatic aneuploidy

  • NORAD functions as a potent molecular decoy for PUMILIO proteins (PUM1/PUM2)

  • PUM1/PUM2 repress a program of genes necessary to maintain genomic stability


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 mRNAs 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.

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