scholarly journals Importance of base-pair opening for mismatch recognition

2020 ◽  
Vol 48 (20) ◽  
pp. 11322-11334
Author(s):  
Tomáš Bouchal ◽  
Ivo Durník ◽  
Viktor Illík ◽  
Kamila Réblová ◽  
Petr Kulhánek
Keyword(s):  
Base Pair ◽  
Computational Study ◽  
Minor Groove ◽  
Base Pairs ◽  
Theoretical Support ◽  
Molecular Pattern ◽  
Anti Cancer ◽  
Mismatch Recognition ◽  
Base Pair Opening

Abstract Mismatch repair is a highly conserved cellular pathway responsible for repairing mismatched dsDNA. Errors are detected by the MutS enzyme, which most likely senses altered mechanical property of damaged dsDNA rather than a specific molecular pattern. While the curved shape of dsDNA in crystallographic MutS/DNA structures suggests the role of DNA bending, the theoretical support is not fully convincing. Here, we present a computational study focused on a base-pair opening into the minor groove, a specific base-pair motion observed upon interaction with MutS. Propensities for the opening were evaluated in terms of two base-pair parameters: Opening and Shear. We tested all possible base pairs in anti/anti, anti/syn and syn/anti orientations and found clear discrimination between mismatches and canonical base-pairs only for the opening into the minor groove. Besides, the discrimination gap was also confirmed in hotspot and coldspot sequences, indicating that the opening could play a more significant role in the mismatch recognition than previously recognized. Our findings can be helpful for a better understanding of sequence-dependent mutability. Further, detailed structural characterization of mismatches can serve for designing anti-cancer drugs targeting mismatched base pairs.

Three-centre C—H...O hydrogen bonds in the DNA minor groove: analysis of oligonucleotide crystal structures

1999 ◽  
Vol 55 (12) ◽  
pp. 2005-2012 ◽  
Author(s):  
Anirban Ghosh ◽  
Manju Bansal
Keyword(s):  
Hydrogen Bonds ◽  
Crystal Structures ◽  
Base Pair ◽  
Minor Groove ◽  
Local Geometry ◽  
Data Sets ◽  
Base Pairs ◽  
Dna Minor Groove ◽  
Close Proximity ◽  
Using Data

AA·TT and GA·TC dinucleotide steps in B-DNA-type oligomeric crystal structures and in protein-bound DNA fragments (solved using data with resolution <2.6 Å) show very small variations in their local dinucleotide geometries. A detailed analysis of these crystal structures reveals that in AA·TT and GA·TC steps the electropositive C2—H2 group of adenine is in very close proximity to the keto O atoms of both the pyrimidine bases in the antiparallel strand of the duplex structure, suggesting the possibility of intra-base pair as well as cross-strand inter-base pair C—H...O hydrogen bonds in the DNA minor groove. The C2—H2...O2 hydrogen bonds in the A·T base pairs could be a natural consequence of Watson–Crick pairing. However, the cross-strand interactions between the bases at the 3′-end of the AA·TT and GA·TC steps obviously arise owing to specific local geometry of these steps, since a majority of the H2...O2 distances in both data sets are considerably shorter than their values in the uniform fibre model (3.3 Å) and many are even smaller than the sum of the van der Waals radii. The analysis suggests that in addition to already documented features such as the large propeller twist of A·T base pairs and the hydration of the minor groove, these C2—H2...O2 cross-strand interactions may also play a role in the narrowing of the minor groove in A-tract regions of DNA and help explain the high structural rigidity and stability observed for poly(dA)·poly(dT).

scholarly journals Differential Stabilities and Sequence-Dependent Base Pair Opening Dynamics of Watson–Crick Base Pairs with 5-Hydroxymethylcytosine, 5-Formylcytosine, or 5-Carboxylcytosine

Biochemistry ◽  
2015 ◽  
Vol 54 (5) ◽  
pp. 1294-1305 ◽  
Author(s):  
Marta W. Szulik ◽  
Pradeep S. Pallan ◽  
Boguslaw Nocek ◽  
Markus Voehler ◽  
Surajit Banerjee ◽  
...  
Keyword(s):  
Base Pair ◽  
Base Pairs ◽  
Sequence Dependent ◽  
Base Pair Opening

scholarly journals Asymmetric base-pair opening drives helicase unwinding dynamics

2019 ◽  
Vol 116 (45) ◽  
pp. 22471-22477 ◽  
Author(s):  
Francesco Colizzi ◽  
Cibran Perez-Gonzalez ◽  
Remi Fritzen ◽  
Yaakov Levy ◽  
Malcolm F. White ◽  
...  
Keyword(s):  
Base Pair ◽  
Double Helix ◽  
The Other ◽  
Base Pairs ◽  
Dna Helicases ◽  
Cellular Processes ◽  
Dna Base ◽  
Dna Base Pairs ◽  
Opening And Closing ◽  
Base Pair Opening

The opening of a Watson–Crick double helix is required for crucial cellular processes, including replication, repair, and transcription. It has long been assumed that RNA or DNA base pairs are broken by the concerted symmetric movement of complementary nucleobases. By analyzing thousands of base-pair opening and closing events from molecular simulations, here, we uncover a systematic stepwise process driven by the asymmetric flipping-out probability of paired nucleobases. We demonstrate experimentally that such asymmetry strongly biases the unwinding efficiency of DNA helicases toward substrates that bear highly dynamic nucleobases, such as pyrimidines, on the displaced strand. Duplex substrates with identical thermodynamic stability are thus shown to be more easily unwound from one side than the other, in a quantifiable and predictable manner. Our results indicate a possible layer of gene regulation coded in the direction-dependent unwindability of the double helix.

Deprotonated guanine·cytosine and 9-methylguanine·cytosine base pairs and their “non-statistical” kinetics: a combined guided-ion beam and computational study

2016 ◽  
Vol 18 (47) ◽  
pp. 32222-32237 ◽  
Author(s):  
Wenchao Lu ◽  
Jianbo Liu
Keyword(s):  
Proton Transfer ◽  
Base Pair ◽  
Computational Study ◽  
Ion Beam ◽  
Base Pairs ◽  
Guided Ion Beam ◽  
Kinetics Of

The intra-base-pair proton transfer and non-RRKM unimolecular kinetics of deprotonated guanine·cytosine base pairs.

scholarly journals Crystal structure of unusual RNA duplex containing strontium ion binding motif

2014 ◽  
Vol 70 (a1) ◽  
pp. C1378-C1378
Author(s):  
Hiroki Kanazawa ◽  
Jiro Kondo
Keyword(s):  
Crystal Structure ◽  
Hydrogen Bonds ◽  
Base Pair ◽  
Binding Pocket ◽  
Minor Groove ◽  
Diffusion Method ◽  
Ion Binding ◽  
Binding Motif ◽  
Base Pairs ◽  
Strontium Ion

Crystal structures of several functional non-coding RNAs, such as ribozymes, aptamers, ribosomes and tRNAs, have been reported so far. Unusual structural motifs and non-complementary base pairs are important for their functions. In the present study, we have determined a crystal structure of an unusual RNA duplex containing a strontium ion binding motif. A 19 mer RNA (5'-UUGUCGCUU[Br]CGAAAAAGUC-3') was chemical synthesized and purified by denaturing PAGE. Crystallizations were performed by the sitting-drop vapor diffusion method. The initial phase was solved by the SAD method. Atomic parameters were refined at a resolution of 3.0 Å. The 19 mer RNA forms an unusual antiparallel duplex. At both ends of the duplex, the Watson-Crick G=C and A-U and the Wobble GoU and AoC base pairs are formed. The Wobble C10oA14* pair is available only in acidic condition by protonation of N1 of A14* (* indicates residues of the opposite strand). Two hydrogen bonds, N1-H(A14*)...O2(C10) and N6-H(A14*)...N3(C10), are observed in the base pair. In the center of the duplex, two sheared G11oA13* and G11*oA13 base pairs are formed. The distance between two RNA chains becomes shorter by the GoA base pair and hydrogen bonds between the Watson-Crick edge of G11 and the phosphate group of A12*. Therefore, the central A12 residue cannot make a base pair, but it makes a stacking interaction with A12*. The A12 residue stacks also with A13 of the sheared GoA base pair. As a result, an A13-A12-A12*-A13* stacked column is formed at the minor groove of the duplex, and the G11 base of the sheared GoA base pair is inclined toward the minor groove. By taking such a unique structure, the RNA duplex has a Sr2+ ion binding pocket in the center. A hydrated Sr2+ ion binds to O6 and N7 of G11 and G11*. The Sr2+ ion is surrounded by four phosphate groups of two RNA chains. The Sr2+ ion is tightly captured by eight hydrogen bonds in total.

scholarly journals Mismatch Recognition by Saccharomyces cerevisiae Msh2-Msh6: Role of Structure and Dynamics

2019 ◽  
Vol 20 (17) ◽  
pp. 4271
Author(s):  
Yan Li ◽  
Zane Lombardo ◽  
Meera Joshi ◽  
Manju M. Hingorani ◽  
Ishita Mukerji
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Rotational Correlation Time ◽  
Base Pairs ◽  
Protein Targets ◽  
Base Analog ◽  
Mismatch Recognition ◽  
Fluorescent Nucleoside ◽  
Peak Emission ◽  
Local Base

The mismatch repair (MMR) pathway maintains genome integrity by correcting errors such as mismatched base pairs formed during DNA replication. In MMR, Msh2–Msh6, a heterodimeric protein, targets single base mismatches and small insertion/deletion loops for repair. By incorporating the fluorescent nucleoside base analog 6-methylisoxanthopterin (6-MI) at or adjacent to a mismatch site to probe the structural and dynamic elements of the mismatch, we address how Msh2–Msh6 recognizes these mismatches for repair within the context of matched DNA. Fluorescence quantum yield and rotational correlation time measurements indicate that local base dynamics linearly correlate with Saccharomyces cerevisiae Msh2–Msh6 binding affinity where the protein exhibits a higher affinity (KD ≤ 25 nM) for mismatches that have a significant amount of dynamic motion. Energy transfer measurements measuring global DNA bending find that mismatches that are both well and poorly recognized by Msh2–Msh6 experience the same amount of protein-induced bending. Finally, base-specific dynamics coupled with protein-induced blue shifts in peak emission strongly support the crystallographic model of directional binding, in which Phe 432 of Msh6 intercalates 3′ of the mismatch. These results imply an important role for local base dynamics in the initial recognition step of MMR.

scholarly journals High Base Pair Opening Rates in Tracts of GC Base Pairs

1999 ◽  
Vol 274 (11) ◽  
pp. 6957-6962 ◽  
Author(s):  
Utz Dornberger ◽  
Mikael Leijon ◽  
Hartmut Fritzsche
Keyword(s):  
Base Pair ◽  
Base Pairs ◽  
High Base ◽  
Base Pair Opening

scholarly journals The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

2021 ◽  
Vol 11 ◽  
Author(s):  
Vijay Kumar
Keyword(s):  
Immune System ◽  
Inflammatory Diseases ◽  
Base Pairs ◽  
Lectin Receptors ◽  
Inflammatory Conditions ◽  
Molecular Pattern ◽  
Self Tolerance ◽  
Evolution Characteristics

The immune system has evolved to protect the host from the pathogens and allergens surrounding their environment. The immune system develops in such a way to recognize self and non-self and develops self-tolerance against self-proteins, nucleic acids, and other larger molecules. However, the broken immunological self-tolerance leads to the development of autoimmune or autoinflammatory diseases. Pattern-recognition receptors (PRRs) are expressed by immunological cells on their cell membrane and in the cytosol. Different Toll-like receptors (TLRs), Nod-like receptors (NLRs) and absent in melanoma-2 (AIM-2)-like receptors (ALRs) forming inflammasomes in the cytosol, RIG (retinoic acid-inducible gene)-1-like receptors (RLRs), and C-type lectin receptors (CLRs) are some of the PRRs. The DNA-sensing receptor cyclic GMP–AMP synthase (cGAS) is another PRR present in the cytosol and the nucleus. The present review describes the role of ALRs (AIM2), TLR9, and cGAS in recognizing the host cell DNA as a potent damage/danger-associated molecular pattern (DAMP), which moves out to the cytosol from its housing organelles (nucleus and mitochondria). The introduction opens with the concept that the immune system has evolved to recognize pathogens, the idea of horror autotoxicus, and its failure due to the emergence of autoimmune diseases (ADs), and the discovery of PRRs revolutionizing immunology. The second section describes the cGAS-STING signaling pathway mediated cytosolic self-DNA recognition, its evolution, characteristics of self-DNAs activating it, and its role in different inflammatory conditions. The third section describes the role of TLR9 in recognizing self-DNA in the endolysosomes during infections depending on the self-DNA characteristics and various inflammatory diseases. The fourth section discusses about AIM2 (an ALR), which also binds cytosolic self-DNA (with 80–300 base pairs or bp) that inhibits cGAS-STING-dependent type 1 IFN generation but induces inflammation and pyroptosis during different inflammatory conditions. Hence, this trinity of PRRs has evolved to recognize self-DNA as a potential DAMP and comes into action to guard the cellular galaxy. However, their dysregulation proves dangerous to the host and leads to several inflammatory conditions, including sterile-inflammatory conditions autoinflammatory and ADs.

scholarly journals Correction to Differential Stabilities and Sequence-Dependent Base Pair Opening Dynamics of Watson–Crick Base Pairs with 5-Hydroxymethylcytosine, 5-Formylcytosine, or 5-Carboxylcytosine

Biochemistry ◽  
2015 ◽  
Vol 54 (15) ◽  
pp. 2550-2550 ◽  
Author(s):  
Marta W. Szulik ◽  
Pradeep S. Pallan ◽  
Boguslaw Nocek ◽  
Markus Voehler ◽  
Surajit Banerjee ◽  
...  
Keyword(s):  
Base Pair ◽  
Base Pairs ◽  
Sequence Dependent ◽  
Base Pair Opening

An IRMPD spectroscopic and computational study of protonated guanine-containing mismatched base pairs in the gas phase

2020 ◽  
Vol 22 (5) ◽  
pp. 2999-3007
Author(s):  
Ruodi Cheng ◽  
Estelle Loire ◽  
Jonathan Martens ◽  
Travis D. Fridgen
Keyword(s):  
Gas Phase ◽  
Base Pair ◽  
Computational Study ◽  
Base Pairs ◽  
Infrared Multiple Photon Dissociation

Infrared multiple photon dissociation spectroscopy has been used to probe the structures of the three protonated base-pair mismatches containing 9-ethylguanine (9eG) in the gas phase. Some of these protonated base-pairs have been identified in RNA.

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