Noncoding RNA NORAD Regulates Genomic Stability by Sequestering PUMILIO Proteins

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

doi:10.1016/j.cell.2015.12.017

Cited by 695 publications

(737 citation statements)

References 56 publications

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“…Their multiple biological activities depend on association with differentially expressed partners, 29 on posttranslational modifications that can be modulated by growth factors, 30 on PUM stability itself, 13 and also on the presence of RNA sponge that binds and sequesters PUM proteins. 27,28 Our data indicate that PUM1 and PUM2 gene expression levels are also regulated along cell differentiation, being maximal in undifferentiated progenitors.…”

Section: Discussionmentioning

confidence: 85%

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PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells

Naudin

Hattabi

Michelet

et al. 2017

Blood

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Key Points• The RNA regulators PUMILIO sustain HSPC and acute myeloid leukemia cell growth by upregulating FOXP1 expression through direct binding to 2 FOXP1-39UTR PUMILIO-binding elements.• FOXP1 mediates PUMILIO growth-promoting activities by repressing expression of p21 CIP1 and p27 KIP1 cell cycle inhibitors.RNA-binding proteins (RBPs) have emerged as important regulators of invertebrate adult stem cells, but their activities remain poorly appreciated in mammals. Using a short hairpin RNA strategy, we demonstrate here that the 2 mammalian RBPs, PUMILIO (PUM)1 and PUM2, members of the PUF family of posttranscriptional regulators, are essential for hematopoietic stem/progenitor cell (HSPC) proliferation and survival in vitro and in vivo upon reconstitution assays. Moreover, we found that PUM1/2 sustain myeloid leukemic cell growth. Through a proteomic approach, we identified the FOXP1 transcription factor as a new target of PUM1/2. Contrary to its canonical repressive activity, PUM1/2 rather promote FOXP1 expression by a direct binding to 2 canonical PUM responsive elements present in the FOXP1-39 untranslated region (UTR). Expression of FOXP1 strongly correlates with PUM1 and PUM2 levels in primary HSPCs and myeloid leukemia cells. We demonstrate that FOXP1 by itself supports HSPC and leukemic cell growth, thus mimicking PUM activities. Mechanistically, FOXP1 represses the expression of the p212CIP1 and p27 2KIP1 cell cycle inhibitors. Enforced FOXP1 expression reverses shPUM antiproliferative and proapoptotic activities. Altogether, our results reveal a novel regulatory pathway, underscoring a previously unknown and interconnected key role of PUM1/2 and FOXP1 in regulating normal HSPC and leukemic cell growth. (Blood. 2017;129(18):2493-2506

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Section: Discussionmentioning

confidence: 85%

“…18 Unexpectedly, overexpression of PUM1/2 was similarly deleterious for HSPC and leukemic cell survival (data not shown), probably reflecting PUM major contribution to chromosome instability, as recently reported. 27,28 These observations indicate that PUM levels are subjected to fine-tuning to control myeloid cell growth.…”

Section: Discussionmentioning

confidence: 99%

PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells

Naudin

Hattabi

Michelet

et al. 2017

Blood

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“…The same stoichiometric concerns exist for the cytoplasmic functions of lncRNAs and, in general, the roles of cytoplasmic lncRNAs have been less explored. Some cytoplasmic lncRNAs, including the circular lncRNA CDR1as (Memczak et al, 2013) and NORAD (Lee et al, 2016;Tichon et al, 2016), are abundant enough to bind to and affect the function of RNA-binding proteins (Argonaute and Pumilio, respectively) and thereby modulate their ability to regulate their other targets. Other cytoplasmic lncRNAs have been shown to bind and modulate the stability and translation of other RNAs by base-pairing with them (Carrieri et al, 2012;Gong and Maquat, 2011).…”

Section: Trans-acting Rnasmentioning

confidence: 99%

The functions of long noncoding RNAs in development and stem cells

2016

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Eukaryotic genomes are pervasively transcribed, with tens of thousands of RNAs emanating from uni-and bi-directional promoters and from active enhancers. In vertebrates, thousands of loci in each species produce a class of transcripts called long noncoding RNAs (lncRNAs) that are typically expressed at low levels and do not appear to give rise to functional proteins. Substantial numbers of lncRNAs are expressed at specific stages of embryonic development, in many cases from regions flanking key developmental regulators. Here, we review the known biological functions of such lncRNAs and the emerging paradigms of their modes of action. We also provide an overview of the growing arsenal of methods for lncRNA identification, perturbation and functional characterization.

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“…For example, lincRNA-p21 is activated by the tumor suppressor p53, represses the transcription of the genes that interfere with apoptosis, and plays a critical role in p53-mediated apoptosis (12). The long non-coding RNA NORAD is induced after DNA damage, and maintains genomic stability by sequestering PUMILIO proteins (13). We have recently shown that the long non-coding RNA lncUSMycN increases N-Myc mRNA expression by interacting with the RNA-binding protein NonO (14).…”

Section: Introductionmentioning

confidence: 99%

NCYM is upregulated by lncUSMycN and modulates N-Myc expression

Liu

Atmadibrata

Mondal

et al. 2016

International Journal of Oncology

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Abstract. Neuroblastoma is the most common solid tumor in early childhood. Patients with neuroblastoma due to the amplification of a 130-kb genomic DNA region containing the MYCN, MYCN antisense NCYM and lncUSMycN genes show poor prognosis. BET bromodomain inhibitors show anticancer efficacy against neuroblastoma partly by reducing MYCN gene transcription and N-Myc mRNA and protein expression. We have previously shown that the long nocoding RNA lncUSMycN upregulates N-Myc mRNA expression by binding to the RNA-binding protein NonO. In this study, we found that lncUSMycN upregulated NCYM expression, and knockingdown lncUSMycN reduced histone H3 lysine 4 trimethylation, a marker for active gene transcription, at the NCYM gene promoter. NCYM upregulated N-Myc mRNA expression, NCYM RNA formed a complex with NonO protein, and knocking down NCYM expression reduced neuroblastoma cell proliferation. Importantly, treatment with BET bromodomain inhibitors reduced NCYM expression. In human neuroblastoma patients, high levels of NCYM expression in tumor tissues correlated with high levels of N-Myc, NonO and lncUSMycN expression as well as poor patient prognosis. Taken together, our findings suggest that lncUSMycN upregulates NCYM expression by activating its gene transcription, and that NCYM RNA upregulates N-Myc mRNA expression by binding to NonO. Our findings also provide further evidence for the application of BET bromodomain inhibitors for the therapy of neuroblastoma characterized by MYCN/ NCYM gene locus amplification.

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Noncoding RNA NORAD Regulates Genomic Stability by Sequestering PUMILIO Proteins

Cited by 695 publications

References 56 publications

PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells

PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells

The functions of long noncoding RNAs in development and stem cells

NCYM is upregulated by lncUSMycN and modulates N-Myc expression

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