-
International Journal of Molecular... Nov 2023ARGONAUTE (AGO) proteins are key components of the RNA-induced silencing complex (RISC) that mediates gene silencing in eukaryotes. Small-RNA (sRNA) cargoes are... (Review)
Review
ARGONAUTE (AGO) proteins are key components of the RNA-induced silencing complex (RISC) that mediates gene silencing in eukaryotes. Small-RNA (sRNA) cargoes are selectively loaded into different members of the AGO protein family and then target complementary sequences to in-duce transcriptional repression, mRNA cleavage, or translation inhibition. Previous reviews have mainly focused on the traditional roles of AGOs in specific biological processes or on the molecular mechanisms of sRNA sorting. In this review, we summarize the biological significance of canonical sRNA loading, including the balance among distinct sRNA pathways, cross-regulation of different RISC activities during plant development and defense, and, especially, the emerging roles of AGOs in sRNA movement. We also discuss recent advances in novel non-canonical functions of plant AGOs. Perspectives for future functional studies of this evolutionarily conserved eukaryotic protein family will facilitate a more comprehensive understanding of the multi-faceted AGO proteins.
Topics: Argonaute Proteins; Plant Proteins; Plants; RNA-Induced Silencing Complex; RNA, Small Untranslated; MicroRNAs; RNA, Small Interfering
PubMed: 38003244
DOI: 10.3390/ijms242216054 -
Journal of Molecular Biology Aug 2017Nearly every cell in the human body contains a set of programmable gene-silencing proteins named Argonaute. Argonaute proteins mediate gene regulation by small RNAs and... (Review)
Review
Nearly every cell in the human body contains a set of programmable gene-silencing proteins named Argonaute. Argonaute proteins mediate gene regulation by small RNAs and thereby contribute to cellular homeostasis during diverse physiological process, such as stem cell maintenance, fertilization, and heart development. Over the last decade, remarkable progress has been made toward understanding Argonaute proteins, small RNAs, and their roles in eukaryotic biology. Here, we review current understanding of Argonaute proteins from a structural prospective and discuss unanswered questions surrounding this fascinating class of enzymes.
Topics: Argonaute Proteins; Eukaryota; Eukaryotic Cells; RNA Interference
PubMed: 28757069
DOI: 10.1016/j.jmb.2017.07.018 -
RNA Biology Sep 2019Argonaute (Ago) proteins are of key importance in many cellular processes. In eukaryotes, Ago can induce translational repression followed by deadenylation and... (Review)
Review
Argonaute (Ago) proteins are of key importance in many cellular processes. In eukaryotes, Ago can induce translational repression followed by deadenylation and degradation of mRNA molecules through base pairing of microRNAs (miRNAs) with a complementary target on a mRNA sequence. In bacteria, Ago eliminates foreign DNA through base pairing of siDNA (small interfering DNA) with a target on a DNA sequence. Effective targeting activities of Ago require fast recognition of the cognate target sequence among numerous off-target sites. Other target search proteins such as transcription factors (TFs) are known to rely on facilitated diffusion for this goal, but it is undetermined to what extent these small nucleic acid-guided proteins utilize this mechanism. Here, we review recent single-molecule studies on Ago target search. We discuss the consequences of the recent findings on the search mechanism. Furthermore, we discuss the open standing research questions that need to be addressed for a complete picture of facilitated target search by small nucleic acids.
Topics: Argonaute Proteins; Bacteria; Base Sequence; DNA; MicroRNAs; RNA, Messenger; Single Molecule Imaging; Transcription Factors
PubMed: 31068066
DOI: 10.1080/15476286.2019.1616353 -
Cellular Physiology and Biochemistry :... 2017P-Element induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are a type of noncoding RNAs (ncRNAs) and interact with PIWI proteins. piRNAs were primarily described in... (Review)
Review
P-Element induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are a type of noncoding RNAs (ncRNAs) and interact with PIWI proteins. piRNAs were primarily described in the germline, but emerging evidence revealed that piRNAs are expressed in a tissue-specific manner among multiple human somatic tissue types as well and play important roles in transposon silencing, epigenetic regulation, gene and protein regulation, genome rearrangement, spermatogenesis and germ stem-cell maintenance. PIWI proteins were first discovered in Drosophila and they play roles in spermatogenesis, germline stem-cell maintenance, self-renewal, retrotransposons silencing and the male germline mobility control. A growing number of studies have demonstrated that several piRNA and PIWI proteins are aberrantly expressed in various kinds of cancers and may probably serve as a novel biomarker and therapeutic target for cancer treatment. Nevertheless, their specific mechanisms and functions need further investigation. In this review, we discuss about the biogenesis, functions and the emerging role of piRNAs and PIWI proteins in cancer, providing novel insights into the possible applications of piRNAs and PIWI proteins in cancer diagnosis and clinical treatment.
Topics: Animals; Argonaute Proteins; Biomarkers, Tumor; DNA Transposable Elements; Epigenesis, Genetic; Gene Expression Regulation; Humans; Neoplasms; RNA, Small Interfering; Receptors, G-Protein-Coupled
PubMed: 29130960
DOI: 10.1159/000484541 -
Annual Review of Biophysics 2013Small RNA molecules regulate eukaryotic gene expression during development and in response to stresses including viral infection. Specialized ribonucleases and... (Review)
Review
Small RNA molecules regulate eukaryotic gene expression during development and in response to stresses including viral infection. Specialized ribonucleases and RNA-binding proteins govern the production and action of small regulatory RNAs. After initial processing in the nucleus by Drosha, precursor microRNAs (pre-miRNAs) are transported to the cytoplasm, where Dicer cleavage generates mature microRNAs (miRNAs) and short interfering RNAs (siRNAs). These double-stranded products assemble with Argonaute proteins such that one strand is preferentially selected and used to guide sequence-specific silencing of complementary target mRNAs by endonucleolytic cleavage or translational repression. Molecular structures of Dicer and Argonaute proteins, and of RNA-bound complexes, have offered exciting insights into the mechanisms operating at the heart of RNA-silencing pathways.
Topics: Animals; Argonaute Proteins; Cell Nucleus; Cytoplasm; Gene Expression Regulation; Humans; MicroRNAs; RNA Interference; RNA, Small Interfering; Ribonuclease III
PubMed: 23654304
DOI: 10.1146/annurev-biophys-083012-130404 -
International Journal of Molecular... Jul 2015Argonaute (Ago) proteins are key players of nucleic acid-based interference mechanisms. Their domains and structural organization are widely conserved in all three... (Review)
Review
Argonaute (Ago) proteins are key players of nucleic acid-based interference mechanisms. Their domains and structural organization are widely conserved in all three domains of life. However, different Ago proteins display various substrate preferences. While some Ago proteins are able to use several substrates, others are limited to a single one. Thereby, they were demonstrated to act specifically on their preferred substrates. Here, we discuss mechanisms of Ago-mediated silencing in relation to structural and biochemical insights. The combination of biochemical and structural information enables detailed analyses of the complex dynamic interplay between Ago proteins and their substrates. Especially, transient binding data allow precise investigations of structural transitions taking place upon Ago-mediated guide and target binding.
Topics: Amino Acid Sequence; Animals; Argonaute Proteins; Gene Silencing; Humans; Molecular Sequence Data; Protein Conformation
PubMed: 26140373
DOI: 10.3390/ijms160714769 -
Biomolecules Jan 2022piRNAs (PIWI-interacting RNAs) are small non-coding RNAs capable of regulation of transposon and gene expression. piRNAs utilise multiple mechanisms to affect gene... (Review)
Review
piRNAs (PIWI-interacting RNAs) are small non-coding RNAs capable of regulation of transposon and gene expression. piRNAs utilise multiple mechanisms to affect gene expression, which makes them potentially more powerful regulators than microRNAs. The mechanisms by which piRNAs regulate transposon and gene expression include DNA methylation, histone modifications, and mRNA degradation. Genitourinary cancers (GC) are a large group of neoplasms that differ by their incidence, clinical course, biology, and prognosis for patients. Regardless of the GC type, metastatic disease remains a key therapeutic challenge, largely affecting patients' survival rates. Recent studies indicate that piRNAs could serve as potentially useful biomarkers allowing for early cancer detection and therapeutic interventions at the stage of non-advanced tumour, improving patient's outcomes. Furthermore, studies in prostate cancer show that piRNAs contribute to cancer progression by affecting key oncogenic pathways such as PI3K/AKT. Here, we discuss recent findings on biogenesis, mechanisms of action and the role of piRNAs and the associated PIWI proteins in GC. We also present tools that may be useful for studies on the functioning of piRNAs in cancers.
Topics: Argonaute Proteins; Humans; Male; Phosphatidylinositol 3-Kinases; Prognosis; RNA, Small Interfering; Urogenital Neoplasms
PubMed: 35204687
DOI: 10.3390/biom12020186 -
Biochemical Society Transactions Aug 2014Endo-siRNAs (endogenous small-interfering RNAs) have recently emerged as versatile regulators of gene expression. They derive from double-stranded intrinsic transcripts... (Review)
Review
Endo-siRNAs (endogenous small-interfering RNAs) have recently emerged as versatile regulators of gene expression. They derive from double-stranded intrinsic transcripts and are processed by Dicer and associate with Argonaute proteins. In Caenorhabditis elegans, endo-siRNAs are known as 22G and 26G RNAs and are involved in genome protection and gene regulation. Drosophila melanogaster endo-siRNAs are produced with the help of specific Dicer and Argonaute isoforms and play an essential role in transposon control and the protection from viral infections. Biological functions of endo-siRNAs in vertebrates include repression of transposable elements and chromatin organization, as well as gene regulation at the transcriptional and post-transcriptional levels.
Topics: Animals; Argonaute Proteins; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Drosophila melanogaster; RNA, Small Interfering; Ribonuclease III
PubMed: 25110021
DOI: 10.1042/BST20140068 -
Plant Reproduction Jun 2022Meiosis is a specialized cell division that is key for reproduction and genetic diversity in sexually reproducing plants. Recently, different RNA silencing pathways have...
Meiosis is a specialized cell division that is key for reproduction and genetic diversity in sexually reproducing plants. Recently, different RNA silencing pathways have been proposed to carry a specific activity during meiosis, but the pathways involved during this process remain unclear. Here, we explored the subcellular localization of different ARGONAUTE (AGO) proteins, the main effectors of RNA silencing, during male meiosis in Arabidopsis thaliana using immunolocalizations with commercially available antibodies. We detected the presence of AGO proteins associated with posttranscriptional gene silencing (AGO1, 2, and 5) in the cytoplasm and the nucleus, while AGOs associated with transcriptional gene silencing (AGO4 and 9) localized exclusively in the nucleus. These results indicate that the localization of different AGOs correlates with their predicted roles at the transcriptional and posttranscriptional levels and provide an overview of their timing and potential role during meiosis.
Topics: Arabidopsis; Arabidopsis Proteins; Argonaute Proteins; Meiosis
PubMed: 34812935
DOI: 10.1007/s00497-021-00434-z -
Nature Jul 2023In eukaryotes, small RNA guides, such as small interfering RNAs and microRNAs, direct AGO-clade Argonaute proteins to regulate gene expression and defend the genome...
In eukaryotes, small RNA guides, such as small interfering RNAs and microRNAs, direct AGO-clade Argonaute proteins to regulate gene expression and defend the genome against external threats. Only animals make a second clade of Argonaute proteins: PIWI proteins. PIWI proteins use PIWI-interacting RNAs (piRNAs) to repress complementary transposon transcripts. In theory, transposons could evade silencing through target site mutations that reduce piRNA complementarity. Here we report that, unlike AGO proteins, PIWI proteins efficiently cleave transcripts that are only partially paired to their piRNA guides. Examination of target binding and cleavage by mouse and sponge PIWI proteins revealed that PIWI slicing tolerates mismatches to any target nucleotide, including those flanking the scissile phosphate. Even canonical seed pairing is dispensable for PIWI binding or cleavage, unlike plant and animal AGOs, which require uninterrupted target pairing from the seed to the nucleotides past the scissile bond. PIWI proteins are therefore better equipped than AGO proteins to target newly acquired or rapidly diverging endogenous transposons without recourse to new small RNA guides. Conversely, the minimum requirements for PIWI slicing are sufficient to avoid inadvertent silencing of host RNAs. Our results demonstrate the biological advantage of PIWI over AGO proteins in defending the genome against transposons and suggest an explanation for why the piRNA pathway was retained in animal evolution.
Topics: Animals; Mice; Argonaute Proteins; DNA Transposable Elements; Piwi-Interacting RNA; Evolution, Molecular; Gene Silencing; Phosphates; Substrate Specificity
PubMed: 37344600
DOI: 10.1038/s41586-023-06257-4