Noncoding RNA Surveillance: The Ends Justify the Means

ABSTRACT A genome-wide screen for synthetic lethal (SL) interactions with loss of the nuclear exosome cofactors Rrp47/Lrp1 or Air1 identified 3′→5′ exonucleases, the THO complex required for mRNP assembly, and Ynr024w (Mpp6). SL interactions with mpp6Δ were confirmed for rrp47Δ and nuclear exosome component Rrp6. The results of bioinformatic analyses revealed homology between Mpp6 and a human exosome cofactor, underlining the high conservation of the RNA surveillance system. Mpp6 is an RNA binding protein that physically associates with the exosome and was localized throughout the nucleus. The results of functional analyses demonstrated roles for Mpp6 in the surveillance of both pre-rRNA and pre-mRNAs and in the degradation of “cryptic” noncoding RNAs (ncRNAs) derived from intergenic regions and the ribosomal DNA spacer heterochromatin. Strikingly, these ncRNAs are also targeted by other exosome cofactors, including Rrp47, the TRAMP complex (which includes Air1), and the Nrd1/Nab3 complex, and are degraded by both Rrp6 and the core exosome. Heterochromatic transcripts and other ncRNAs are characterized by very rapid degradation, and we predict that functional redundancy is an important feature of ncRNA metabolism.

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Nuclear noncoding RNA surveillance: is the end in sight?

Trends in Genetics ◽

10.1016/j.tig.2012.03.005 ◽

2012 ◽

Vol 28 (7) ◽

pp. 306-313 ◽

Cited By ~ 29

Author(s):

Sandra L. Wolin ◽

Soyeong Sim ◽

Xinguo Chen

Keyword(s):

Noncoding Rna ◽

Rna Surveillance

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Growth Arrest on Inhibition of Nonsense-Mediated Decay Is Mediated by Noncoding RNA GAS5

BioMed Research International ◽

10.1155/2013/358015 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 25

Author(s):

Mirna Mourtada-Maarabouni ◽

Gwyn T. Williams

Keyword(s):

Mammalian Cells ◽

Noncoding Rna ◽

Critical Role ◽

Significant Proportion ◽

Growth Arrest ◽

Nonsense Mediated Decay ◽

Rna Surveillance ◽

Premature Termination Codons ◽

Surveillance Mechanism ◽

Lymphocyte Cell

Nonsense-mediated decay is a key RNA surveillance mechanism responsible for the rapid degradation of mRNAs containing premature termination codons and hence prevents the synthesis of truncated proteins. More recently, it has been shown that nonsense-mediated decay also has broader significance in controlling the expression of a significant proportion of the transcriptome. The importance of this mechanism to the mammalian cell is demonstrated by the observation that its inhibition causes growth arrest. The noncoding RNA growth arrest specific transcript 5 (GAS5) has recently been shown to play a key role in growth arrest induced by several mechanisms, including serum withdrawal and treatment with the mTOR inhibitor rapamycin. Here we show that inhibition of nonsense-mediated decay in several human lymphocyte cell lines causes growth arrest, and siRNA-mediated downregulation of GAS5 in these cells significantly alleviates the inhibitory effects observed. These observations hold true for inhibition of nonsense-mediated decay both through RNA interference and through pharmacological inhibition by aminoglycoside antibiotics gentamycin and G418. These studies have important implications for ototoxicity and nephrotoxicity caused by gentamycin and for the proposed use of NMD inhibition in treating genetic disease. This report further demonstrates the critical role played by GAS5 in the growth arrest of mammalian cells.

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