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 - Funding Information:
We thank Tyler Jacks, Rudolf Jaenisch, Keith Joung, David Root, Didier Trono, and Feng Zhang for plasmids; Kathleen Wilson, Sangeeta Patel, and Charles Tiongson in the Veripath Cytogenetics laboratory at University of Texas Southwestern; Vanessa Schmid, Ashley Guzman, and Rachel Bruce in the McDermott Center Next Generation Sequencing Core; and Hamid Mirzaei and David Trudgian in the University of Texas Southwestern Proteomics Core. Stephen Johnson provided valuable assistance with software implementation. We also thank Jose Cabrera for assistance with figure preparation and Nicholas Conrad, Kathryn O''Donnell, Eric Olson, Hao Zhu, and members of the Mendell laboratory for critical reading of the manuscript. This work was supported by grants from CPRIT (R1008 to J.T.M., RP101251 to Y.X., and RP120717 to H.Y.) and the NIH (R01CA120185 and R35CA197311 to J.T.M. and R01CA152301 to Y.X.). J.T.M. and H.Y. are investigators of the Howard Hughes Medical Institute, J.T.M. is a CPRIT Scholar in Cancer Research, and F.K. is supported by the Leopoldina Fellowship Program (LPDS 2014-12) from the German National Academy of Sciences Leopoldina.
Funding Information:
We thank Tyler Jacks, Rudolf Jaenisch, Keith Joung, David Root, Didier Trono, and Feng Zhang for plasmids; Kathleen Wilson, Sangeeta Patel, and Charles Tiongson in the Veripath Cytogenetics laboratory at University of Texas Southwestern; Vanessa Schmid, Ashley Guzman, and Rachel Bruce in the McDermott Center Next Generation Sequencing Core; and Hamid Mirzaei and David Trudgian in the University of Texas Southwestern Proteomics Core. Stephen Johnson provided valuable assistance with software implementation. We also thank Jose Cabrera for assistance with figure preparation and Nicholas Conrad, Kathryn O’Donnell, Eric Olson, Hao Zhu, and members of the Mendell laboratory for critical reading of the manuscript. This work was supported by grants from CPRIT (R1008 to J.T.M., RP101251 to Y.X., and RP120717 to H.Y.) and the NIH (R01CA120185 and R35CA197311 to J.T.M. and R01CA152301 to Y.X.). J.T.M. and H.Y. are investigators of the Howard Hughes Medical Institute, J.T.M. is a CPRIT Scholar in Cancer Research, and F.K. is supported by the Leopoldina Fellowship Program (LPDS 2014-12) from the German National Academy of Sciences Leopoldina.
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 -