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Regulating the Regulators: Posttranslational Modifications of RNA Silencing Factors
Heo, Inha,Kim, V. Narry Elsevier 2009 Cell Vol.139 No.1
<P>Every regulator should be regulated, and this holds true for small RNAs and their associated proteins. Knowledge has begun to emerge of the various mechanisms that impose specificity on the expression and function of RNA silencing factors. Recent papers, including one in this issue of <I>Cell</I> (<ce:cross-ref refid='bib8'>Paroo et al., 2009</ce:cross-ref>), now reveal the posttranslational modifications that take part in the regulation of the core RNA silencing factors, Ago, Piwi, and TRBP.</P>
Lin28 Mediates the Terminal Uridylation of let-7 Precursor MicroRNA
Heo, Inha,Joo, Chirlmin,Cho, Jun,Ha, Minju,Han, Jinju,Kim, V. Narry Elsevier 2008 Molecular cell Vol.32 No.2
<P><B>Summary</B></P><P>The precise control of microRNA (miRNA) biogenesis is critical for embryonic development and normal cellular functions, and its dysregulation is often associated with human diseases. Though the birth and maturation pathway of miRNA has been established, the regulation and death pathway remains largely unknown. Here, we report the RNA-binding proteins, Lin28a and Lin28b, as posttranscriptional repressors of let-7 miRNA biogenesis. We observe that the Lin28 proteins act mainly in the cytoplasm by inducing uridylation of precursor let-7 (pre-let-7) at its 3′ end. The uridylated pre-let-7 (up-let-7) fails Dicer processing and undergoes degradation. We provide a mechanism for the posttranscriptional regulation of miRNA biogenesis by Lin28 which is highly expressed in undifferentiated cells and certain cancer cells. The Lin28-mediated downregulation of let-7 may play a key role in development, stem cell programming, and tumorigenesis.</P>
TUT4 in Concert with Lin28 Suppresses MicroRNA Biogenesis through Pre-MicroRNA Uridylation
Heo, Inha,Joo, Chirlmin,Kim, Young-Kook,Ha, Minju,Yoon, Mi-Jeong,Cho, Jun,Yeom, Kyu-Hyeon,Han, Jinju,Kim, V. Narry Elsevier 2009 Cell Vol.138 No.4
<P><B>Summary</B></P><P>As key regulators in cellular functions, microRNAs (miRNAs) themselves need to be tightly controlled. Lin28, a pluripotency factor, was reported to downregulate let-7 miRNA by inducing uridylation of let-7 precursor (pre-let-7). But the enzyme responsible for the uridylation remained unknown. Here we identify a noncanonical poly (A) polymerase, TUTase4 (TUT4), as the uridylyl transferase for pre-let-7. Lin28 recruits TUT4 to pre-let-7 by recognizing a tetra-nucleotide sequence motif (GGAG) in the terminal loop. TUT4 in turn adds an oligouridine tail to the pre-let-7, which blocks Dicer processing. Other miRNAs with the same sequence motif (miR-107, -143, and -200c) are regulated through the same mechanism. Knockdown of TUT4 and Lin28 reduces the level of stem cell markers, suggesting that they are required for stem cell maintenance. This study uncovers the role of TUT4 and Lin28 as specific suppressors of miRNA biogenesis, which has implications for stem cell research and cancer biology.</P>
Dicer recognizes the 5' end of RNA for efficient and accurate processing
Park, Jong-Eun,Heo, Inha,Tian, Yuan,Simanshu, Dhirendra K.,Chang, Hyeshik,Jee, David,Patel, Dinshaw J.,Kim, V. Narry Nature Publishing Group, a division of Macmillan P 2011 Nature Vol.475 No.7355
A hallmark of RNA silencing is a class of approximately 22-nucleotide RNAs that are processed from double-stranded RNA precursors by Dicer. Accurate processing by Dicer is crucial for the functionality of microRNAs (miRNAs). The current model posits that Dicer selects cleavage sites by measuring a set distance from the 3′ overhang of the double-stranded RNA terminus. Here we report that human Dicer anchors not only the 3′ end but also the 5′ end, with the cleavage site determined mainly by the distance (~ 2 nucleotides) from the 5′ end (5′ counting rule). This cleavage requires a 5′ terminal phosphate group. Further, we identify a novel basic motif (5′ pocket) in human Dicer that recognizes the 5′ -phosphorylated end. The 5′ counting rule and the 5′ anchoring residues are conserved in Drosophila Dicer-1, but not in Giardia Dicer. Mutations in the 5′ pocket reduce processing efficiency and alter cleavage sites in vitro. Consistently, miRNA biogenesis is perturbed in vivo when Dicer-null embryonic stem cells are replenished with the 5′ pocket mutant. Thus, 5′-end recognition by Dicer is important for precise and effective biogenesis of miRNAs. Insights from this study should also afford practical benefits to the design of small hairpin RNAs.
Modifications of Small RNAs and Their Associated Proteins
Kim, Young-Kook,Heo, Inha,Kim, V. Narry Elsevier 2010 Cell Vol.143 No.5
<P>Small regulatory RNAs and their associated proteins are subject to diverse modifications that can impinge on their abundance and function. Some of the modifications are under the influence of cellular signaling, thus contributing to the dynamic regulation of RNA silencing.</P>
Dongmin Seo,Jieun Kim,Jiwon Kim,Inhae Heo,Jonghwan Moon,Kyoungwon Jung,Hohyung Jung The Korean Society of Traumatology 2024 大韓外傷學會誌 Vol.37 No.1
Inferior vena cava (IVC) injuries can have fatal outcomes and are associated with high mortality rates. Patients with IVC injuries require multiple procedures, including prehospital care, surgical techniques, and postoperative care. We present the case of a 67-year-old woman who stabbed herself in the abdomen with a knife, resulting in an infrarenal IVC injury. We shortened the transfer time by transporting the patient using a helicopter and decided to perform direct-to-operating room resuscitation by a trauma physician in the helicopter. The patient underwent laparotomy with IVC ligation for damage control during the first operation. The second- and third-look operations, including previous suture removal, IVC reconstruction, and IVC thrombectomy, were performed by a trauma surgeon specializing in cardiovascular diseases. The patient was discharged without major complications on the 19th postoperative day with rivaroxaban as an anticoagulant medication. Computed tomography angiography at the outpatient clinic showed that thrombi in the IVC and both iliac veins had been completely removed. Patients with IVC injuries can be effectively treated using a trauma system that includes fast transportation by helicopter, damage control for rapid hemostasis, and expert treatment of IVC injuries.
Human UPF1 Participates in Small RNA-Induced mRNA Downregulation
Jin, Hua,Suh, Mi Ra,Han, Jinju,Yeom, Kyu-Hyeon,Lee, Yoontae,Heo, Inha,Ha, Minju,Hyun, Seogang,Kim, V. Narry American Society for Microbiology 2009 Molecular and cellular biology Vol.29 No.21
<B>ABSTRACT</B><P>MicroRNAs (miRNAs) are endogenous antisense regulators that trigger endonucleolytic mRNA cleavage, translational repression, and/or mRNA decay. miRNA-mediated gene regulation is important for numerous biological pathways, yet the underlying mechanisms are still under rigorous investigation. Here we identify human UPF1 (hUPF1) as a protein that contributes to RNA silencing. When hUPF1 is knocked down, miRNA targets are upregulated. The depletion of hUPF1 also increases the off-target messages of small interfering RNAs (siRNAs), which are imperfectly complementary to transfected siRNAs. Conversely, when overexpressed, wild-type hUPF1 downregulates miRNA targets. The helicase domain mutant of hUPF1 fails to suppress miRNA targets. hUPF1 interacts with human Argonaute 1 (hAGO1) and hAGO2 and colocalizes with hAGO1 and hAGO2 in processing bodies, which are known to be the sites for translational repression and mRNA destruction. We further find that the amounts of target messages bound to hAGO2 are reduced when hUPF1 is depleted. Our data thus suggest that hUPF1 may participate in RNA silencing by facilitating the binding of the RNA-induced silencing complex to the target and by accelerating the decay of the mRNA.</P>