-
RNA Biology Feb 2018DROSHA is the catalytic subunit of the Microprocessor complex, which initiates microRNA (miRNA) maturation in the nucleus by recognizing and cleaving hairpin precursors...
DROSHA is the catalytic subunit of the Microprocessor complex, which initiates microRNA (miRNA) maturation in the nucleus by recognizing and cleaving hairpin precursors embedded in primary transcripts. However, accumulating evidence suggests that not all hairpin substrates of DROSHA are associated with the generation of functional small RNAs. By targeting those hairpins, DROSHA regulates diverse aspects of RNA metabolism across the transcriptome, serves as a line of defense against the expression of potentially deleterious elements, and permits cell fate determination and differentiation. DROSHA is also versatile in the way that it executes these noncanonical functions, occasionally depending on its RNA-binding activity rather than its catalytic activity. Herein, we discuss the functional and mechanistic diversity of DROSHA beyond the miRNA biogenesis pathway in light of recent findings.
Topics: Animals; Cell Differentiation; Humans; MicroRNAs; RNA Processing, Post-Transcriptional; Ribonuclease III
PubMed: 29171328
DOI: 10.1080/15476286.2017.1405210 -
Advances in Clinical and Experimental... 2016Hepatocellular carcinoma is one of the deadliest types of cancer. Despite improvements in treatment over the past few decades, patient survival remains poor and there is... (Review)
Review
Hepatocellular carcinoma is one of the deadliest types of cancer. Despite improvements in treatment over the past few decades, patient survival remains poor and there is an urgent need for development of targeted therapies. MicroRNAs represent a class of small RNAs, frequently deregulated in human malignancies. We are reviewing the role of microRNA in the development of primary hepatocellular carcinoma and its use as a biomarker for early diagnosis and clinical treatment. First, we describe the current incidence and possible causes of the incidence of hepatocellular carcinoma, followed by the introduction of microRNA synthesis, maturation and function, and finally we explain the role of microRNA in the development of hepatocellular carcinoma and its clinical value as a biological marker in the diagnosis and treatment of liver cancer. A comprehensive analysis of cellular microRNA is a benefit for early diagnosis of hepatocellular carcinoma and early clinical intervention, and microRNA is considered by some to be a key target of gene therapy to control the occurrence and development of hepatocellular carcinoma..
Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; MicroRNAs; Neoplasm Metastasis
PubMed: 28028963
DOI: 10.17219/acem/36460 -
Genes & Development May 2023DROSHA serves as a gatekeeper of the microRNA (miRNA) pathway by processing primary transcripts (pri-miRNAs). While the functions of structured domains of DROSHA have...
DROSHA serves as a gatekeeper of the microRNA (miRNA) pathway by processing primary transcripts (pri-miRNAs). While the functions of structured domains of DROSHA have been well documented, the contribution of N-terminal proline-rich disordered domain (PRD) remains elusive. Here we show that the PRD promotes the processing of miRNA hairpins located within introns. We identified a DROSHA isoform (p140) lacking the PRD, which is produced by proteolytic cleavage. Small RNA sequencing revealed that p140 is significantly impaired in the maturation of intronic miRNAs. Consistently, our minigene constructs demonstrated that PRD enhances the processing of intronic hairpins, but not those in exons. Splice site mutations did not affect the PRD's enhancing effect on intronic constructs, suggesting that the PRD acts independently of splicing reaction by interacting with sequences residing within introns. The N-terminal regions from zebrafish and DROSHA can replace the human counterpart, indicating functional conservation despite poor sequence alignment. Moreover, we found that rapidly evolving intronic miRNAs are generally more dependent on PRD than conserved ones, suggesting a role of PRD in miRNA evolution. Our study reveals a new layer of miRNA regulation mediated by a low-complexity disordered domain that senses the genomic contexts of miRNA loci.
Topics: Animals; Humans; Introns; MicroRNAs; Proline; Ribonuclease III; RNA Processing, Post-Transcriptional; Zebrafish
PubMed: 37236670
DOI: 10.1101/gad.350275.122 -
Frontiers in Immunology 2022Wound healing, a highly complex pathophysiological response to injury, includes four overlapping phases of hemostasis, inflammation, proliferation, and remodeling.... (Review)
Review
Wound healing, a highly complex pathophysiological response to injury, includes four overlapping phases of hemostasis, inflammation, proliferation, and remodeling. Initiation and resolution of the inflammatory response are the primary requirements for wound healing, and are also key events that determines wound quality and healing time. Currently, the number of patients with persistent chronic wounds has generally increased, which imposes health and economic burden on patients and society. Recent studies have found that microRNA(miRNA) plays an essential role in the inflammation involved in wound healing and may provide a new therapeutic direction for wound treatment. Therefore, this review focused on the role and significance of miRNA in the inflammation phase of wound healing.
Topics: Humans; Inflammation; MicroRNAs; Wound Healing
PubMed: 35386721
DOI: 10.3389/fimmu.2022.852419 -
Trends in Cell Biology Jan 2010The expression of protein-coding genes is enhanced by the exquisite coupling of transcription by RNA polymerase II with pre-messenger RNA processing reactions, such as... (Review)
Review
The expression of protein-coding genes is enhanced by the exquisite coupling of transcription by RNA polymerase II with pre-messenger RNA processing reactions, such as 5'-end capping, splicing and 3'-end formation. Integration between cotranscriptional processing events extends beyond the nucleus, as proteins that bind cotranscriptionally can affect the localization, translation and degradation of the mature messenger RNA. MicroRNAs are RNA polymerase II transcripts with crucial roles in the regulation of gene expression. Recent data demonstrate that processing of primary microRNA transcripts might be yet another cotranscriptional event that is woven into this elaborate nuclear network. This review discusses the extensive molecular interactions that couple the earliest steps in gene expression and therefore influence the final fate and function of the mature messenger RNA or microRNA produced.
Topics: Animals; Cell Nucleus; Gene Regulatory Networks; Humans; MicroRNAs; RNA Precursors; RNA Splicing; Transcription, Genetic
PubMed: 20004579
DOI: 10.1016/j.tcb.2009.10.004 -
Cancer Metastasis Reviews Dec 2019Abdominal tumors (AT) in children account for approximately 17% of all pediatric solid tumor cases, and frequently exhibit embryonal histological features that... (Review)
Review
Abdominal tumors (AT) in children account for approximately 17% of all pediatric solid tumor cases, and frequently exhibit embryonal histological features that differentiate them from adult cancers. Current molecular approaches have greatly improved the understanding of the distinctive pathology of each tumor type and enabled the characterization of novel tumor biomarkers. As seen in abdominal adult tumors, microRNAs (miRNAs) have been increasingly implicated in either the initiation or progression of childhood cancer. Moreover, besides predicting patient prognosis, they represent valuable diagnostic tools that may also assist the surveillance of tumor behavior and treatment response, as well as the identification of the primary metastatic sites. Thus, the present study was undertaken to compile up-to-date information regarding the role of dysregulated miRNAs in the most common histological variants of AT, including neuroblastoma, nephroblastoma, hepatoblastoma, hepatocarcinoma, and adrenal tumors. Additionally, the clinical implications of dysregulated miRNAs as potential diagnostic tools or indicators of prognosis were evaluated.
Topics: Abdominal Neoplasms; Animals; Child; Humans; MicroRNAs
PubMed: 31848768
DOI: 10.1007/s10555-019-09829-x -
Molecular Therapy : the Journal of the... May 2023Repeated use of opioids such as morphine causes changes in the shape and signal transduction pathways of various brain cells, including astrocytes and neurons,...
Repeated use of opioids such as morphine causes changes in the shape and signal transduction pathways of various brain cells, including astrocytes and neurons, resulting in alterations in brain functioning and ultimately leading to opioid use disorder. We previously demonstrated that extracellular vesicle (EV)-induced primary ciliogenesis contributes to the development of morphine tolerance. Herein, we aimed to investigate the underlying mechanisms and potential EV-mediated therapeutic approach to inhibit morphine-mediated primary ciliogenesis. We demonstrated that miRNA cargo in morphine-stimulated-astrocyte-derived EVs (morphine-ADEVs) mediated morphine-induced primary ciliogenesis in astrocytes. CEP97 is a target of miR-106b and is a negative regulator of primary ciliogenesis. Intranasal delivery of ADEVs loaded with anti-miR-106b decreased the expression of miR-106b in astrocytes, inhibited primary ciliogenesis, and prevented the development of tolerance in morphine-administered mice. Furthermore, we confirmed primary ciliogenesis in the astrocytes of opioid abusers. miR-106b-5p in morphine-ADEVs induces primary ciliogenesis via targeting CEP97. Intranasal delivery of ADEVs loaded with anti-miR-106b ameliorates morphine-mediated primary ciliogenesis and prevents morphine tolerance. Our findings bring new insights into the mechanisms underlying primary cilium-mediated morphine tolerance and pave the way for developing ADEV-mediated small RNA delivery strategies for preventing substance use disorders.
Topics: Mice; Animals; Antagomirs; Morphine; MicroRNAs; Brain; Extracellular Vesicles
PubMed: 37012704
DOI: 10.1016/j.ymthe.2023.03.030 -
The Journal of Biological Chemistry 2021miRNAs are important regulators of eukaryotic gene expression. The post-transcriptional maturation of miRNAs is controlled by the Drosha-DiGeorge syndrome critical...
miRNAs are important regulators of eukaryotic gene expression. The post-transcriptional maturation of miRNAs is controlled by the Drosha-DiGeorge syndrome critical region gene 8 (DGCR8) microprocessor. Dysregulation of miRNA biogenesis has been implicated in the pathogenesis of human diseases, including cancers. C-terminal-binding protein-interacting protein (CtIP) is a well-known DNA repair factor that promotes the processing of DNA double-strand break (DSB) to initiate homologous recombination-mediated DSB repair. However, it was unclear whether CtIP has other unknown cellular functions. Here, we aimed to uncover the roles of CtIP in miRNA maturation and cancer cell metastasis. We found that CtIP is a potential regulatory factor that suppresses the processing of miRNA primary transcripts (pri-miRNA). CtIP directly bound to both DGCR8 and pri-miRNAs through a conserved Sae2-like domain, reduced the binding of Drosha to DGCR8 and pri-miRNA substrate, and inhibited processing activity of Drosha complex. CtIP depletion significantly increased the expression levels of a subset of mature miRNAs, including miR-302 family members that are associated with tumor progression and metastasis in several cancer types. We also found that CtIP-inhibited miRNAs, such as miR-302 family members, are not crucial for DSB repair. However, increase of miR-302b levels or loss of CtIP function severely suppressed human colon cancer cell line tumor cell metastasis in a mouse xenograft model. These studies reveal a previously unrecognized mechanism of CtIP in miRNA processing and tumor metastasis that represents a new function of CtIP in cancer.
Topics: Animals; Cell Line, Tumor; Cell Transformation, Neoplastic; Colonic Neoplasms; Endodeoxyribonucleases; Humans; Mice; MicroRNAs; Neoplasm Metastasis; Proto-Oncogene Proteins pp60(c-src)
PubMed: 33901493
DOI: 10.1016/j.jbc.2021.100707 -
Methods in Molecular Biology (Clifton,... 2006The miRBase Sequence database is the primary repository for published microRNA (miRNA) sequence and annotation data. miRBase provides a user-friendly web interface for... (Review)
Review
The miRBase Sequence database is the primary repository for published microRNA (miRNA) sequence and annotation data. miRBase provides a user-friendly web interface for miRNA data, allowing the user to search using key words or sequences, trace links to the primary literature referencing the miRNA discoveries, analyze genomic coordinates and context, and mine relationships between miRNA sequences. miRBase also provides a confidential gene-naming service, assigning official miRNA names to novel genes before their publication. The methods outlined in this chapter describe these functions. miRBase is freely available to all at http://microrna.sanger.ac.uk/.
Topics: Animals; Base Sequence; Databases, Nucleic Acid; Genomics; Humans; Internet; MicroRNAs; Molecular Sequence Data; Sequence Analysis, RNA; Sequence Homology, Nucleic Acid; Terminology as Topic; User-Computer Interface
PubMed: 16957372
DOI: 10.1385/1-59745-123-1:129 -
Fertility and Sterility Jun 2014MicroRNAs, also called miRNAs, are small 19-22 nucleotide (nt) sequences of noncoding RNA that work as endogenous epigenetic gene expression regulators. They are... (Review)
Review
MicroRNAs, also called miRNAs, are small 19-22 nucleotide (nt) sequences of noncoding RNA that work as endogenous epigenetic gene expression regulators. They are transcribed as large primary miRNAs or pre-miRNAs by RNA polymerase II and III, and are subsequently processed by the ribonucleases Drosha and Dicer to give rise to their mature forms. These mature miRNAs are then incorporated into the RISC complex (RNA-induced silencing complex) where they bind to the 3'-UTR mRNA complementary region, which induces their degradation or inhibits their translation, resulting in gene silencing. MicroRNAs are essential for embryo, cell, and tissue development, regulating cell differentiation, proliferation, and apoptosis, hence their importance in human reproduction. Currently, methods of detecting these molecules include real-time polymerase chain reaction, microarrays, in situ hybridization, and deep sequencing as well as novel approaches such as Nanostring nCounter. However, functional characterization is still required to confirm their biologic roles. Furthermore, miRNAs are not only found in cells but also have been identified in most biologic fluids, including serum, plasma, and saliva. Once miRNAs are secreted by cells, they are either incorporated into microvesicles or become associated with proteins, which protect them from RNase degradation so that they may remain intact for long periods of time. This suggests that they might also mediate paracrine signaling via different pathways and could therefore represent potential new biomarkers. Indeed, many pharmaceutic companies have recently started to investigate these molecules as possible routes to develop new human disease treatments.
Topics: Animals; Gene Expression Regulation; Genetic Markers; Genetic Therapy; Humans; MicroRNAs; Signal Transduction; Terminology as Topic
PubMed: 24314918
DOI: 10.1016/j.fertnstert.2013.10.042