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Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex
- Cell
, 2006
"... The Drosha-DGCR8 complex initiates micro-RNA maturation by precise cleavage of the stem loops that are embedded in primary transcripts (pri-miRNAs). Here we propose a model for this process that is based upon evidence from both computational and biochemical analyses. A typical metazoan pri-miRNA con ..."
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The Drosha-DGCR8 complex initiates micro-RNA maturation by precise cleavage of the stem loops that are embedded in primary transcripts (pri-miRNAs). Here we propose a model for this process that is based upon evidence from both computational and biochemical analyses. A typical metazoan pri-miRNA consists of a stem of 33 bp, with a terminal loop and flanking segments. The terminal loop is unessential, whereas the flanking ssRNA segments are critical for processing. The cleavage site is determined mainly by the distance ( 11 bp) from the stem-ssRNA junction. Purified DGCR8, but not Drosha, interacts with pri-miRNAs both directly and specifically, and the flanking ssRNA segments are vital for this binding to occur. Thus, DGCR8 may function as the molecular anchor that measures the distance from the dsRNA-ssRNA junction. Our current study thus facilitates the prediction of novel micro-RNAs and will assist in the rational design of small hairpin RNAs for RNA interference.
CONTRAfold: RNA secondary structure prediction without physics-based models
- Bioinformatics
, 2006
"... doi:10.1093/bioinformatics/btl246 ..."
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Sfold web server for statistical folding and rational design of nucleic acids
- Nucleic Acids Res
, 2004
"... nucleic acids ..."
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Pure multiple RNA secondary structure alignments: a progressive profile approach
- IEEE/ACM Trans. Comput. Biol. Bioinform
"... Abstract—In functional, noncoding RNA, structure is often essential to function. While the full 3D structure is very difficult to determine, the 2D structure of an RNA molecule gives good clues to its 3D structure, and for molecules of moderate length, it can be predicted with good reliability. Stru ..."
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Cited by 73 (3 self)
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Abstract—In functional, noncoding RNA, structure is often essential to function. While the full 3D structure is very difficult to determine, the 2D structure of an RNA molecule gives good clues to its 3D structure, and for molecules of moderate length, it can be predicted with good reliability. Structure comparison is, in analogy to sequence comparison, the essential technique to infer related function. We provide a method for computing multiple alignments of RNA secondary structures under the tree alignment model, which is suitable to cluster RNA molecules purely on the structural level, i.e., sequence similarity is not required. We give a systematic generalization of the profile alignment method from strings to trees and forests. We introduce a tree profile representation of RNA secondary structure alignments which allows reasonable scoring in structure comparison. Besides the technical aspects, an RNA profile is a useful data structure to represent multiple structures of RNA sequences. Moreover, we propose a visualization of RNA consensus structures that is enriched by the full sequence information. Index Terms—Alignment of trees, RNA secondary structures, noncoding RNAs.
Molecular basis for target RNA recognition and cleavage by human RISC. Cell 130:101–112
, 2007
"... a ribonucleoprotein particle composed of a single-stranded short interfering RNA (siRNA) and an endonucleolytically active Argonaute protein, capable of cleaving mRNAs complementary to the siRNA. The mechanism by which RISC cleaves a target RNA is well understood, however it remains enigmatic how RI ..."
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Cited by 70 (0 self)
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a ribonucleoprotein particle composed of a single-stranded short interfering RNA (siRNA) and an endonucleolytically active Argonaute protein, capable of cleaving mRNAs complementary to the siRNA. The mechanism by which RISC cleaves a target RNA is well understood, however it remains enigmatic how RISC finds its target RNA. Here, we show, both in vitro and in vivo, that the accessibility of the target site correlates directly with the efficiency of cleavage, demonstrating that RISC is unable to unfold structured RNA. In the course of target recognition, RISC transiently contacts singlestranded RNA nonspecifically and promotes siRNA-target RNA annealing. Furthermore, the 5 0 part of the siRNA within RISC creates a thermodynamic threshold that determines the stable association of RISC and the target RNA. We therefore provide mechanistic insights by revealing features of RISC and target RNAs that are crucial to achieve efficiency and specificity in RNA interference.
Thermodynamics of RNA-RNA Binding
, 2005
"... Background: Reliable predictions of RNA-RNA binding energies is crucial e.g. for the understanding on RNAi, microRNA-mRNA binding, and antisense interactions. The thermodynamics of such RNA-RNA interactions can be understood as the sum of two energy contributions: (1) the energy necessary to “open ” ..."
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Cited by 66 (14 self)
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Background: Reliable predictions of RNA-RNA binding energies is crucial e.g. for the understanding on RNAi, microRNA-mRNA binding, and antisense interactions. The thermodynamics of such RNA-RNA interactions can be understood as the sum of two energy contributions: (1) the energy necessary to “open ” the binding site, and (2) the energy gained from hybridization. Methods: We present an extension of the standard partition function approach to RNA secondary structures that computes the probabilities Pu[i, j] that a sequence interval [i, j] is unpaired. Results: Comparison with experimental data shows that Pu[i, j] can be applied as a significant determinant of local target site accessibility for RNA interference (RNAi). Furthermore, these quantities can be used to rigorously determine binding free energies of short oligomers to large mRNA targets. The resource consumption is comparable to a single partition function computation for the large target molecule. We can show that RNAi efficiency correlates well with the binding energies of siRNAs to their respective mRNA target.
Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA
- Hum. Mol. Genet
, 2007
"... mature miR-125a alters the processing of pri-miRNA ..."
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mature miR-125a alters the processing of pri-miRNA
Influence of RNA secondary structure on the pre-mRNA splicing process
- Mol. Cell. Biol
, 2004
"... This article cites 108 articles, 57 of which can be accessed free ..."
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Cited by 61 (8 self)
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This article cites 108 articles, 57 of which can be accessed free
HIV-1 can escape from RNA interference by evolving an alternative structure in its RNA genome
- Nucleic Acids Res
, 2005
"... HIV-1 replication can be efficiently inhibited by intra-cellular expression of an siRNA targeting the viral RNA. However, HIV-1 escape variants emerged after prolonged culturing. These RNAi-resistant viruses contain nucleotide substitutions or deletions in or near the targeted sequence. We observed ..."
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Cited by 57 (14 self)
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HIV-1 replication can be efficiently inhibited by intra-cellular expression of an siRNA targeting the viral RNA. However, HIV-1 escape variants emerged after prolonged culturing. These RNAi-resistant viruses contain nucleotide substitutions or deletions in or near the targeted sequence. We observed an inverse correlation between the level of resistance and the stability of the siRNA/target-RNA duplex. However, two escape variants showed a higher level of resist-ance than expected based on the duplex stability. We demonstrate that these mutations induce alternative folding of the RNA such that the target sequence is occluded from binding to the siRNA, resulting in reduced RNAi efficiency. HIV-1 can thus escape from RNAi-mediated inhibition not only through nuc-leotide substitutions or deletions in the siRNA target sequence, but also through mutations that alter the local RNA secondary structure. The results highlight the enormous genetic flexibility of HIV-1 and provide detailed molecular insight into the sequence specifi-city of RNAi and the impact of target RNA secondary structure.
Centroid estimation in discrete highdimensional spaces with applications
- in biology,” Proceedings of the National Academy of Sciences
, 2008
"... in biology ..."
