TY - JOUR
T1 - Noncoding RNA NORAD Regulates Genomic Stability by Sequestering PUMILIO Proteins
AU - Lee, Sungyul
AU - Kopp, Florian
AU - Chang, Tsung Cheng
AU - Sataluri, Anupama
AU - Chen, Beibei
AU - Sivakumar, Sushama
AU - Yu, Hongtao
AU - Xie, Yang
AU - Mendell, Joshua T.
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/1/14
Y1 - 2016/1/14
N2 - 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.
AB - 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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U2 - 10.1016/j.cell.2015.12.017
DO - 10.1016/j.cell.2015.12.017
M3 - Article
C2 - 26724866
AN - SCOPUS:84954399183
SN - 0092-8674
VL - 164
SP - 69
EP - 80
JO - Cell
JF - Cell
IS - 1-2
ER -