rna duplexes
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2021 ◽  
Author(s):  
Long-Fei Wu ◽  
Ziwei Liu ◽  
Samuel J Roberts ◽  
Meng Su ◽  
Jack W Szostak ◽  
...  

RNA hairpin loops are the predominant element of secondary structure in functional RNAs. The emergence of primordial functional RNAs, such as ribozymes that fold into complex structures that contain multiple hairpin loops, is generally thought to have been supported by template-directed ligation. However, template inhibition and RNA misfolding problems impede the emergence of function. Here we demonstrate that RNA hairpin loops can be synthesized directly from short RNA duplexes with single-stranded overhangs by nonenzymatic loop-closing ligation chemistry. We show that loop-closing ligation allows full-length functional ribozymes containing a hairpin loop to be assembled free of inhibitory template strands. This approach to the assembly of structurally complex RNAs suggests a plausible pathway for the emergence of functional RNAs before a full-length RNA copying process became available.


2021 ◽  
pp. 100231
Author(s):  
Ryo Tsukimura ◽  
Ryohei Kajino ◽  
Yujun Zhou ◽  
Akash Chandela ◽  
Yoshihito Ueno

2021 ◽  
Vol 22 (18) ◽  
pp. 9708
Author(s):  
Wayne K. Dawson ◽  
Amiu Shino ◽  
Gota Kawai ◽  
Ella Czarina Morishita

For the last 20 years, it has been common lore that the free energy of RNA duplexes formed from canonical Watson–Crick base pairs (bps) can be largely approximated with dinucleotide bp parameters and a few simple corrective constants that are duplex independent. Additionally, the standard benchmark set of duplexes used to generate the parameters were GC-rich in the shorter duplexes and AU-rich in the longer duplexes, and the length of the majority of the duplexes ranged between 6 and 8 bps. We were curious if other models would generate similar results and whether adding longer duplexes of 17 bps would affect the conclusions. We developed a gradient-descent fitting program for obtaining free-energy parameters—the changes in Gibbs free energy (ΔG), enthalpy (ΔH), and entropy (ΔS), and the melting temperature (Tm)—directly from the experimental melting curves. Using gradient descent and a genetic algorithm, the duplex melting results were combined with the standard benchmark data to obtain bp parameters. Both the standard (Turner) model and a new model that includes length-dependent terms were tested. Both models could fit the standard benchmark data; however, the new model could handle longer sequences better. We developed an updated strategy for fitting the duplex melting data.


BBA Advances ◽  
2021 ◽  
pp. 100025
Author(s):  
Norman H.L. Chiu ◽  
Jennifer H. Simpson ◽  
Hongzhou Wang ◽  
Bakhos A. Tannous

Author(s):  
Ahmed Mostafa Abdelhady ◽  
Yu Hirano ◽  
Kazumitsu Onizuka ◽  
Hidenori Okamura ◽  
Yasuo Komatsu ◽  
...  

2021 ◽  
Vol 7 (17) ◽  
pp. eabf6106
Author(s):  
Weiwei He ◽  
Yen-Lin Chen ◽  
Lois Pollack ◽  
Serdal Kirmizialtin

Double-stranded DNA (dsDNA) and RNA (dsRNA) helices display an unusual structural diversity. Some structural variations are linked to sequence and may serve as signaling units for protein-binding partners. Therefore, elucidating the mechanisms and factors that modulate these variations is of fundamental importance. While the structural diversity of dsDNA has been extensively studied, similar studies have not been performed for dsRNA. Because of the increasing awareness of RNA’s diverse biological roles, such studies are timely and increasingly important. We integrate solution x-ray scattering at wide angles (WAXS) with all-atom molecular dynamics simulations to explore the conformational ensemble of duplex topologies for different sequences and salt conditions. These tightly coordinated studies identify robust correlations between features in the WAXS profiles and duplex geometry and enable atomic-level insights into the structural diversity of DNA and RNA duplexes. Notably, dsRNA displays a marked sensitivity to the valence and identity of its associated cations.


2021 ◽  
Vol 402 (5) ◽  
pp. 653-661
Author(s):  
Karsten Weis

Abstract DEAD-box ATPase proteins are found in all clades of life and have been associated with a diverse array of RNA-processing reactions in eukaryotes, bacteria and archaea. Their highly conserved core enables them to bind RNA, often in an ATP-dependent manner. In the course of the ATP hydrolysis cycle, they undergo conformational rearrangements, which enable them to unwind short RNA duplexes or remodel RNA-protein complexes. Thus, they can function as RNA helicases or chaperones. However, when their conformation is locked, they can also clamp RNA and create ATP-dependent platforms for the formation of higher-order ribonucleoprotein complexes. Recently, it was shown that DEAD-box ATPases globally regulate the phase-separation behavior of RNA-protein complexes in vitro and control the dynamics of RNA-containing membraneless organelles in both pro- and eukaryotic cells. A role of these enzymes as regulators of RNA-protein condensates, or ‘condensases’, suggests a unifying view of how the biochemical activities of DEAD-box ATPases are used to keep cellular condensates dynamic and ‘alive’, and how they regulate the composition and fate of ribonucleoprotein complexes in different RNA processing steps.


2021 ◽  
Author(s):  
Kuohan Li ◽  
Jie Zheng ◽  
Melissa Wirawan ◽  
Trinh Mai Nguyen ◽  
Olga Fedorova ◽  
...  

DRH-3 belongs to the family of duplex RNA-dependent ATPases (DRAs), which include Dicer and RIG-I-like receptors (RLRs). DRH-3 is critically involved in germline development and RNAi-facilitated chromosome segregation via the 22G-siRNA pathway in C. elegans. The molecular understanding of DRH-3 and its function in endogenous RNAi pathways remains elusive. In this study, we solved the crystal structures of the DRH-3 N-terminal domain (NTD) and the C-terminal domains (CTDs) in complex with 5'-triphosphorylated RNAs. The NTD of DRH-3 adopts a distinct fold of tandem Caspase Activation and Recruitment Domains (CARDs) structurally similar to the CARDs of RIG-I and MDA5, suggesting a signaling function in the endogenous RNAi biogenesis. The CTD preferentially recognizes 5'-triphosphorylated double-stranded RNAs bearing the typical features of secondary siRNA transcripts. The full-length DRH-3 displays unique structural dynamics upon binding to RNA duplexes that differ from RIG-I or MDA5. These unique molecular features of DRH-3 help explain its function in RNAi in worms and the evolutionary divergence of the Dicer-like helicases.


2021 ◽  
Author(s):  
Lingdi Zhang ◽  
Timothy A Vickers ◽  
Hong Sun ◽  
Xue-hai Liang ◽  
Stanley T Crooke

Abstract We recently found that toxic PS-ASOs can cause P54nrb and PSF nucleolar mislocalization in an RNase H1-dependent manner. To better understand the underlying mechanisms of these observations, here we utilize different biochemical approaches to demonstrate that PS-ASO binding can alter the conformations of the bound proteins, as illustrated using recombinant RNase H1, P54nrb, PSF proteins and various isolated domains. While, in general, binding of PS-ASOs or ASO/RNA duplexes stabilizes the conformations of these proteins, PS-ASO binding may also cause the unfolding of RNase H1, including both the hybrid binding domain and the catalytic domain. The extent of conformational change correlates with the binding affinity of PS-ASOs to the proteins. Consequently, PS-ASO binding to RNase H1 induces the interaction of RNase H1 with P54nrb or PSF in a 2′-modification and sequence dependent manner, and toxic PS-ASOs tend to induce more interactions than non-toxic PS-ASOs. PS-ASO binding also enhances the interaction between P54nrb and PSF. However, the interaction between RNase H1 and P32 protein can be disrupted upon binding of PS-ASOs. Together, these results suggest that stronger binding of PS-ASOs can cause greater conformational changes of the bound proteins, subsequently affecting protein–protein interactions. These observations thus provide deeper understanding of the molecular basis of PS-ASO-induced protein mislocalization or degradation observed in cells and advance our understanding of why some PS-ASOs are cytotoxic.


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