Long noncoding‐RNA component of mitochondrial RNA processing endoribonuclease is involved in the progression of cholangiocarcinoma by regulating microRNA‐217

AbstractBackgroundMitogenome diversity is staggering among early branching animals with respect to size, gene density and content, gene orders, and number of tRNA genes, especially in cnidarians. This last point is of special interest as tRNA cleavage drives the maturation of mitochondrial mRNAs and is a primary mechanism for mt-RNA processing in animals. Mitochondrial RNA processing in non-bilaterian metazoans, some of which possess a single tRNA gene in their mitogenomes, is essentially unstudied despite its importance in understanding the evolution of mitochondrial transcription in animals.ResultsWe characterized the mature mitochondrial mRNA transcripts in a species of the octocoral genus Sinularia (Alcyoniidae: Octocorallia), and defined precise boundaries of transcription units using different molecular methods. Most mt-mRNAs were polycistronic units containing two or three genes and 5’ and/or 3’ untranslated regions (UTRs) of varied length. The octocoral specific, mtDNA-encoded mismatch repair gene, mtMutS, was found to undergo alternative polyadenylation (APA), and exhibited differential expression of alternate transcripts suggesting a unique regulatory mechanism for this gene. In addition, a long noncoding RNA complementary to the ATP6 gene (lncATP6) potentially involved in antisense regulation was detected.ConclusionsMt-mRNA processing in octocorals bearing a single mt-tRNA is complex. Considering the variety of mitogenome arrangements known in cnidarians, and in general among non-bilaterian metazoans, our findings provide a first glimpse into the complex mtDNA transcription, mt-mRNA processing, and regulation among early branching animals and represents a first step towards understanding its functional and evolutionary implications.

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ARS2 Regulates Nuclear Paraspeckle Formation through 3′-End Processing and Stability of NEAT1 Long Noncoding RNA

Molecular and Cellular Biology ◽

10.1128/mcb.00269-19 ◽

2019 ◽

Vol 40 (4) ◽

Author(s):

Mitsuhiro Machitani ◽

Ichiro Taniguchi ◽

Mutsuhito Ohno

Keyword(s):

Rna Polymerase ◽

Rna Polymerase Ii ◽

Rna Processing ◽

Long Noncoding Rna ◽

Crucial Role ◽

Noncoding Rna ◽

Subsequent Formation ◽

Factor I ◽

Cap Binding Complex ◽

Resistance Protein

ABSTRACT Nuclear paraspeckle assembly transcript 1 (NEAT1) is a long noncoding RNA that functions as an essential framework of subnuclear paraspeckle bodies. Of the two isoforms (NEAT1_1 and NEAT1_2) produced by alternative 3′-end RNA processing, the longer isoform, NEAT1_2, plays a crucial role in paraspeckle formation. Here, we demonstrate that the 3′-end processing and stability of NEAT1 RNAs are regulated by arsenic resistance protein 2 (ARS2), a factor interacting with the cap-binding complex (CBC) that binds to the m7G cap structure of RNA polymerase II transcripts. The knockdown of ARS2 inhibited the association between NEAT1 and mammalian cleavage factor I (CFIm), which produces the shorter isoform, NEAT1_1. Furthermore, the knockdown of ARS2 led to the preferential stabilization of NEAT1_2. As a result, NEAT1_2 RNA levels were markedly elevated in ARS2 knockdown cells, leading to an increase in the number of paraspeckles. These results reveal a suppressive role for ARS2 in NEAT1_2 expression and the subsequent formation of paraspeckles.

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Inactivation of the tumor suppressor p53 by long noncoding RNA RMRP

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2026813118 ◽

2021 ◽

Vol 118 (29) ◽

pp. e2026813118

Author(s):

Yajie Chen ◽

Qian Hao ◽

Shanshan Wang ◽

Mingming Cao ◽

Yingdan Huang ◽

...

Keyword(s):

Colorectal Cancer ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Mitochondrial Rna ◽

Tumor Resistance ◽

Factor C

p53 inactivation is highly associated with tumorigenesis and drug resistance. Here, we identify a long noncoding RNA, the RNA component of mitochondrial RNA-processing endoribonuclease (RMRP), as an inhibitor of p53. RMRP is overexpressed and associated with an unfavorable prognosis in colorectal cancer. Ectopic RMRP suppresses p53 activity by promoting MDM2-induced p53 ubiquitination and degradation, while depletion of RMRP activates the p53 pathway. RMRP also promotes colorectal cancer growth and proliferation in a p53-dependent fashion in vitro and in vivo. This anti-p53 action of RMRP is executed through an identified partner protein, SNRPA1. RMRP can interact with SNRPA1 and sequester it in the nucleus, consequently blocking its lysosomal proteolysis via chaperone-mediated autophagy. The nuclear SNRPA1 then interacts with p53 and enhances MDM2-induced proteasomal degradation of p53. Remarkably, ablation of SNRPA1 completely abrogates RMRP regulation of p53 and tumor cell growth, indicating that SNRPA1 is indispensable for the anti-p53 function of RMRP. Interestingly and significantly, poly (ADP-ribose) polymerase (PARP) inhibitors induce RMRP expression through the transcription factor C/EBPβ, and RMRP confers tumor resistance to PARP inhibition by preventing p53 activation. Altogether, our study demonstrates that RMRP plays an oncogenic role by inactivating p53 via SNRPA1 in colorectal cancer.

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The long noncoding RNA of RMRP is downregulated by PERK, which induces apoptosis in hepatocellular carcinoma cells

Scientific Reports ◽

10.1038/s41598-021-86592-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Atsushi Yukimoto ◽

Takao Watanabe ◽

Kotaro Sunago ◽

Yoshiko Nakamura ◽

Takaaki Tanaka ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Transcriptome Analysis ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Chronic Liver ◽

Mitochondrial Rna

AbstractEndoplasmic reticulum (ER) stress plays an important role in hepatocyte degeneration, especially in patients with chronic liver injury. Protein kinase R-like endoplasmic reticulum kinase (PERK) is a key molecule in ER stress. PERK may contribute to apoptotic cell death in HCC, however the details of the mechanism are not clear. In this study, we identified PERK-associated molecules using transcriptome analysis. We modulated PERK expression using a plasmid, tunicamycin and siRNA against PERK, and then confirmed the target gene expression with real-time PCR and Northern blotting. We further analyzed the apoptotic function. Transcriptome analysis revealed that expression of the RNA component of mitochondrial RNA processing endoribonuclease (RMRP), which is a long noncoding RNA, was strongly correlated with the function of PERK. The expression of RMRP was correlated with the expression of PERK in experiments with the siRNA and PERK plasmid in both HCC cell lines and human HCC tissue. Furthermore, RMRP downregulation induced apoptotic cell death. RMRP is downregulated by PERK, which induces apoptosis in HCC. RMRP could be a new therapeutic target to regulate HCC in patients with chronic liver diseases associated with ER stress.

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