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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 18269

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Prof. Dr. Masayuki Takahashi

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Guest Editor

School of Life Science and Technology, Tokyo Institute of Technology, Tokyo 152-8550, Japan
Interests: molecular mechanism of homologous recombination; anti-cancer drug design
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Protein/DNA interactions are crucial to many cellular processes such as gene expression, replication, DNA repair, DNA compaction, and regulations. There are different types of interaction upon their dependence on the nucleotide sequence, the structure, etc. Various approaches have been developed to study these protein/DNA interactions to understand their critical functions. They include structural analyses, molecular simulations, biochemical studies, mutation analyses, single-molecule observations, etc. The study clarified how proteins recognize their specific target DNA and modify DNA structure for the reaction.

The study also revealed that many protein/DNA interactions are regulated by protein/protein interactions. The formation of multiprotein complexes is required to regulate gene expression or DNA repair. Chromatin remodeling factors play an essential role in eukaryotic cells where DNA is compacted in chromatins. Exciting progress has been made to analyze these multi-protein/DNA interactions and investigate protein-DNA interactions inside cells in the crowded and complex molecular environment.

This special issue is intended to provide a forum to discuss protein-DNA interactions from broader perspectives, ranging from an atomic/molecular level to a cellular/organismic level. Review articles by experts in the field are particularly welcomed.

We invite you to contribute to your research, extending our current knowledge about protein/DNA interaction and the approaches used for such studies. It is an interesting topic since it produces new avenues for understanding fundamental biological processes and new therapies for diseases based on aberrant gene expression and DNA modification.

Prof. Dr. Masayuki Takahashi
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

protein-DNA interactions
gene expression
DNA replication
DNA repair
homologous recombination
macromolecular crowding
chromatin structure
epigenetics

Related Special Issue

Protein and DNA Interactions 2.0 in International Journal of Molecular Sciences (3 articles)

Published Papers (10 papers)

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Research

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17 pages, 5490 KiB

Open AccessArticle

Broadly Applicable Control Approaches Improve Accuracy of ChIP-Seq Data

by Meghan V. Petrie, Yiwei He, Yan Gan, Andrew Zachary Ostrow and Oscar M. Aparicio

Int. J. Mol. Sci. 2023, 24(11), 9271; https://doi.org/10.3390/ijms24119271 - 25 May 2023

Viewed by 1334

Abstract

Chromatin ImmunoPrecipitation (ChIP) is a widely used method for the analysis of protein–DNA interactions in vivo; however, ChIP has pitfalls, particularly false-positive signal enrichment that permeates the data. We have developed a new approach to control for non-specific enrichment in ChIP that involves the expression of a non-genome-binding protein targeted in the IP alongside the experimental target protein due to the sharing of epitope tags. ChIP of the protein provides a “sensor” for non-specific enrichment that can be used for the normalization of the experimental data, thereby correcting for non-specific signals and improving data quality as validated against known binding sites for several proteins that we tested, including Fkh1, Orc1, Mcm4, and Sir2. We also tested a DNA-binding mutant approach and showed that, when feasible, ChIP of a site-specific DNA-binding mutant of the target protein is likely an ideal control. These methods vastly improve our ChIP-seq results in S. cerevisiae and should be applicable in other systems. Full article

(This article belongs to the Special Issue Protein and DNA Interaction)

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20 pages, 4835 KiB

Open AccessArticle

Comparative Analysis of Molecular Functions and Biological Role of Proteins from Cell-Free DNA-Protein Complexes Circulating in Plasma of Healthy Females and Breast Cancer Patients

by Oleg Tutanov, Aleksei Shefer, Yuri Tsentalovich and Svetlana Tamkovich

Int. J. Mol. Sci. 2023, 24(8), 7279; https://doi.org/10.3390/ijms24087279 - 14 Apr 2023

Cited by 1 | Viewed by 1406

Abstract

Cell-free DNA (cfDNA) circulates in the bloodstream packed in membrane-coated structures (such as apoptotic bodies) or bound to proteins. To identify proteins involved in the formation of deoxyribonucleoprotein complexes circulating in the blood, native complexes were isolated using affinity chromatography with immobilized polyclonal anti-histone antibodies from plasma of healthy females (HFs) and breast cancer patients (BCPs). It was found that the nucleoprotein complexes (NPCs) from HF plasma samples contained shorter DNA fragments (~180 bp) than BCP NPCs. However, the share of DNA in the NPCs from cfDNA in blood plasma in HFs and BCPs did not differ significantly, as well as the share of NPC protein from blood plasma total protein. Proteins were separated by SDS-PAGE and identified by MALDI-TOF mass spectrometry. Bioinformatic analysis showed that in the presence of a malignant tumor, the proportion of proteins involved in ion channels, protein binding, transport, and signal transduction increased in the composition of blood-circulating NPCs. Moreover, 58 (35%) proteins are differentially expressed in a number of malignant neoplasms in the NPCs of BCPs. Identified NPC proteins from BCP blood can be recommended for further testing as breast cancer diagnostic/prognostic biomarkers or as being useful in developing gene-targeted therapy approaches. Full article

(This article belongs to the Special Issue Protein and DNA Interaction)

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14 pages, 4336 KiB

Open AccessArticle

Micromechanical Study of Hyperacetylated Nucleosomes Using Single Molecule Transverse Magnetic Tweezers

by Santosh Gaire, Roberto L. Fabian, Jr., Raghabendra Adhikari, Pamela L. Tuma, Ian L. Pegg and Abhijit Sarkar

Int. J. Mol. Sci. 2023, 24(7), 6188; https://doi.org/10.3390/ijms24076188 - 24 Mar 2023

Cited by 3 | Viewed by 1387

Abstract

Nucleosomes are stable complexes of DNA and histone proteins that are essential for the proper functioning of the genome. These structures must be unwrapped and disassembled for processes such as gene expression, replication, and repair. Histone post-translational modifications (PTMs) are known to play a significant role in regulating the structural changes of nucleosomes. However, the underlying mechanisms by which these modifications function remain unclear. In this study, we report the results of single molecule micromanipulation experiments on DNA–protein complexes composed of hyperacetylated histone proteins using transverse magnetic tweezers. The experiments were conducted by pre-extending λ-DNA with a force less than 4

pN

before introducing hyperacetylated histones into the sample chamber. The DNA shortened as the histones formed complexes with it and the nucleosome arrays were then exposed to increasing tension, resulting in quantized changes in the DNA’s extension with step sizes of (integral multiples of) ~50

nm

. We also compared results of experiments using PTM histones and native histones with data collected for both types of histones for the same force ranges (2–80

pN

) and loading rates. Our data show that hyperacetylated nucleosomes require an unbinding force of around ~2.5

pN

, which is similar to that required for native histones. Moreover, we identified clear differences between the step-size distributions of native and hyperacetylated histones and found that in contrast to tethers reconstituted with native histones, the majority of nucleosomes in tethers compacted with hyperacetylated histones underwent disassembly at forces significantly lower than 6

pN

. Full article

(This article belongs to the Special Issue Protein and DNA Interaction)

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14 pages, 2474 KiB

Open AccessArticle

Structural Insights of the DciA Helicase Loader in Its Relationship with DNA

by Claire Cargemel, Sonia Baconnais, Magali Aumont-Nicaise, Magali Noiray, Lia Maurin, Jessica Andreani, Hélène Walbott, Eric Le Cam, Françoise Ochsenbein, Stéphanie Marsin and Sophie Quevillon-Cheruel

Int. J. Mol. Sci. 2023, 24(2), 1427; https://doi.org/10.3390/ijms24021427 - 11 Jan 2023

Viewed by 1562

Abstract

DciA is the ancestral bacterial replicative helicase loader, punctually replaced during evolution by the DnaC/I loaders of phage origin. DnaC helps the helicase to load onto DNA by cracking open the hexameric ring, but the mechanism of loading by DciA remains unknown. We demonstrate by electron microscopy, nuclear magnetic resonance (NMR) spectroscopy, and biochemistry experiments that DciA, which folds into a KH-like domain, interacts with not only single-stranded but also double-stranded DNA, in an atypical mode. Some point mutations of the long α-helix 1 demonstrate its importance in the interaction of DciA for various DNA substrates mimicking single-stranded, double-stranded, and forked DNA. Some of these mutations also affect the loading of the helicase by DciA. We come to the hypothesis that DciA could be a DNA chaperone by intercalating itself between the two DNA strands to stabilize it. This work allows us to propose that the direct interaction of DciA with DNA could play a role in the loading mechanism of the helicase. Full article

(This article belongs to the Special Issue Protein and DNA Interaction)

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17 pages, 3018 KiB

Open AccessArticle

Complementary Roles of Two DNA Protection Proteins from Deinococcus geothermalis

by Min K. Bae, Eunjung Shin and Sung-Jae Lee

Int. J. Mol. Sci. 2023, 24(1), 469; https://doi.org/10.3390/ijms24010469 - 27 Dec 2022

Cited by 1 | Viewed by 1692

Abstract

The roles of two interrelated DNA protection protein in starved cells (Dps)—putative Dps Dgeo_0257 and Dgeo_0281—as orthologous proteins to DrDps1 for DNA binding, protection, and metal ion sensing were characterised in a Deinococcus geothermalis strain. Dgeo_0257 exhibited high DNA-binding affinity and formed a multimeric structure but lacked the conserved amino acid sequence for ferroxidase activity. In contrast, the Dgeo_0281 (DgDps1) protein was abundant in the early exponential phase, had a lower DNA-binding activity than Dgeo_0257, and was mainly observed in its monomeric or dimeric forms. Electrophoretic mobility shift assays demonstrated that both purified proteins bound nonspecifically to DNA, and their binding ability was affected by certain metal ions. For example, in the presence of ferrous and ferric ions, neither Dgeo_0257 nor Dgeo_0281 could readily bind to DNA. In contrast, both proteins exhibited more stable DNA binding in the presence of zinc and manganese ions. Mutants in which the dps gene was disrupted exhibited higher sensitivity to oxidative stress than the wild-type strain. Furthermore, the expression levels of each gene showed an opposite correlation under H₂O₂ treatment conditions. Collectively, these findings indicate that the putative Dps Dgeo_0257 and DgDps1 from D. geothermalis are involved in DNA binding and protection in complementary interplay ways compared to known Dps. Full article

(This article belongs to the Special Issue Protein and DNA Interaction)

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18 pages, 4000 KiB

Open AccessArticle

Analytical Perspectives in the Study of Polyvalent Interactions of Free and Surface-Bound Oligonucleotides and Their Implications in Affinity Biosensing

by Laura-Elena Gliga, Bogdan-Cezar Iacob, Sanda-Nastasia Moldovean, David A. Spivak, Andreea Elena Bodoki, Ede Bodoki and Radu Oprean

Int. J. Mol. Sci. 2023, 24(1), 175; https://doi.org/10.3390/ijms24010175 - 22 Dec 2022

Cited by 1 | Viewed by 1357

Abstract

The high affinity and/or selectivity of oligonucleotide-mediated binding offers a myriad of therapeutical and analytical applications, whose rational design implies an accurate knowledge of the involved molecular mechanisms, concurring equilibrium processes and key affinity parameters. Oligonucleotide-functionalized gold surfaces or nanostructures are regularly employed analytical platforms for the development of label-free optical or electrochemical biosensors, and recently, novel detection platform designs have been increasingly considering the synergistic effect of polyvalent binding, involving the simultaneous interaction of two or several oligonucleotide strands. Considering the general lack of studies involving ternary single-stranded DNA (ssDNA) interactions, a complementary analytical workflow involving capillary gel electrophoretic (CGE) mobility shift assay, microcalorimetry and computational modeling has been deployed for the characterization of a series of free and surface-bound binary and ternary oligonucleotide interactions. As a proof of concept, the DNA analogue of MicroRNA 21 (miR21), a well-known oncogenic short MicroRNA (miRNA) sequence, has been chosen as a target molecule, simulating limiting-case scenarios involved in dual molecular recognition models exploited in affinity (bio)sensing. Novel data for the characterization of oligonucleotide interacting modules is revealed, offering a fast and complete mapping of the specific or non-specific, often competing, binary and ternary order interactions in dynamic equilibria, occurring between various free and metal surface-bound oligonucleotides. Full article

(This article belongs to the Special Issue Protein and DNA Interaction)

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14 pages, 2971 KiB

Open AccessArticle

EBF1 Negatively Regulates Brassinosteroid-Induced Apical Hook Development and Cell Elongation through Promoting BZR1 Degradation

by Na Zhao, Min Zhao, Lingyan Wang, Chao Han, Mingyi Bai and Min Fan

Int. J. Mol. Sci. 2022, 23(24), 15889; https://doi.org/10.3390/ijms232415889 - 14 Dec 2022

Cited by 3 | Viewed by 1456

Abstract

Brassinosteroids (BRs) are a group of plant steroid hormones that play important roles in a wide range of developmental and physiological processes in plants. Transcription factors BRASSINOZALE-RESISTANT1 (BZR1) and its homologs are key components of BR signaling and integrate a wide range of internal and environmental signals to coordinate plant growth and development. Although several E3 ligases have been reported to regulate the stability of BZR1, the molecular mechanism of BZR1 degradation remains unclear. Here, we reveal how a newly identified molecular mechanism underlying EBF1 directly regulates BZR1 protein stability via the 26S proteasome pathway, repressing BR function on regulating Arabidopsis apical hook development and hypocotyl elongation. BZR1 directly binds to the EBF1 gene promotor to reduce EBF1 expression. Furthermore, the genetic analysis shows that BZR1, EIN3 and PIF4 interdependently regulate plant apical hook development. Taken together, our data demonstrates that EBF1 is a negative regulator of the BR signaling pathway. Full article

(This article belongs to the Special Issue Protein and DNA Interaction)

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16 pages, 2538 KiB

Open AccessArticle

Structural Basis of Mutation-Dependent p53 Tetramerization Deficiency

by Marta Rigoli, Giovanni Spagnolli, Giulia Lorengo, Paola Monti, Raffaello Potestio, Emiliano Biasini and Alberto Inga

Int. J. Mol. Sci. 2022, 23(14), 7960; https://doi.org/10.3390/ijms23147960 - 19 Jul 2022

Cited by 2 | Viewed by 2915

Abstract

The formation of a tetrameric assembly is essential for the ability of the tumor suppressor protein p53 to act as a transcription factor. Such a quaternary conformation is driven by a specific tetramerization domain, separated from the central DNA-binding domain by a flexible linker. Despite the distance, functional crosstalk between the two domains has been reported. This phenomenon can explain the pathogenicity of some inherited or somatically acquired mutations in the tetramerization domain, including the widespread R337H missense mutation present in the population in south Brazil. In this work, we combined computational predictions through extended all-atom molecular dynamics simulations with functional assays in a genetically defined yeast-based model system to reveal structural features of p53 tetramerization domains and their transactivation capacity and specificity. In addition to the germline and cancer-associated R337H and R337C, other rationally designed missense mutations targeting a significant salt-bridge interaction that stabilizes the p53 tetramerization domain were studied (i.e., R337D, D352R, and the double-mutation R337D plus D352R). The simulations revealed a destabilizing effect of the pathogenic mutations within the p53 tetramerization domain and highlighted the importance of electrostatic interactions between residues 337 and 352. The transactivation assay, performed in yeast by tuning the expression of wild-type and mutant p53 proteins, revealed that p53 tetramerization mutations could decrease the transactivation potential and alter transactivation specificity, in particular by better tolerating negative features in weak DNA-binding sites. These results establish the effect of naturally occurring variations at positions 337 and 352 on p53’s conformational stability and function. Full article

(This article belongs to the Special Issue Protein and DNA Interaction)

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18 pages, 2214 KiB

Open AccessReview

Cracking the Floral Quartet Code: How Do Multimers of MIKC^C-Type MADS-Domain Transcription Factors Recognize Their Target Genes?

by Sandra Käppel, Florian Rümpler and Günter Theißen

Int. J. Mol. Sci. 2023, 24(9), 8253; https://doi.org/10.3390/ijms24098253 - 4 May 2023

Cited by 4 | Viewed by 1909

Abstract

MADS-domain transcription factors (MTFs) are involved in the control of many important processes in eukaryotes. They are defined by the presence of a unique and highly conserved DNA-binding domain, the MADS domain. MTFs bind to double-stranded DNA as dimers and recognize specific sequences termed CArG boxes (such as 5′-CC(A/T)₆GG-3′) and similar sequences that occur hundreds of thousands of times in a typical flowering plant genome. The number of MTF-encoding genes increased by around two orders of magnitude during land plant evolution, resulting in roughly 100 genes in flowering plant genomes. This raises the question as to how dozens of different but highly similar MTFs accurately recognize the cis-regulatory elements of diverse target genes when the core binding sequence (CArG box) occurs at such a high frequency. Besides the usual processes, such as the base and shape readout of individual DNA sequences by dimers of MTFs, an important sublineage of MTFs in plants, termed MIKC^C-type MTFs (M^C-MTFs), has evolved an additional mechanism to increase the accurate recognition of target genes: the formation of heterotetramers of closely related proteins that bind to two CArG boxes on the same DNA strand involving DNA looping. M^C-MTFs control important developmental processes in flowering plants, ranging from root and shoot to flower, fruit and seed development. The way in which M^C-MTFs bind to DNA and select their target genes is hence not only of high biological interest, but also of great agronomic and economic importance. In this article, we review the interplay of the different mechanisms of target gene recognition, from the ordinary (base readout) via the extravagant (shape readout) to the idiosyncratic (recognition of the distance and orientation of two CArG boxes by heterotetramers of M^C-MTFs). A special focus of our review is on the structural prerequisites of M^C-MTFs that enable the specific recognition of target genes. Full article

(This article belongs to the Special Issue Protein and DNA Interaction)

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21 pages, 1869 KiB

Open AccessReview

The Ros/MucR Zinc-Finger Protein Family in Bacteria: Structure and Functions

by Monika Janczarek

Int. J. Mol. Sci. 2022, 23(24), 15536; https://doi.org/10.3390/ijms232415536 - 8 Dec 2022

Cited by 4 | Viewed by 2051

Abstract

Ros/MucR is a widespread family of bacterial zinc-finger-containing proteins that integrate multiple functions, such as symbiosis, virulence, transcription regulation, motility, production of surface components, and various other physiological processes in cells. This regulatory protein family is conserved in bacteria and is characterized by its zinc-finger motif, which has been proposed as the ancestral domain from which the eukaryotic C₂H₂ zinc-finger structure has evolved. The first prokaryotic zinc-finger domain found in the transcription regulator Ros was identified in Agrobacterium tumefaciens. In the past decades, a large body of evidence revealed Ros/MucR as pleiotropic transcriptional regulators that mainly act as repressors through oligomerization and binding to AT-rich target promoters. The N-terminal domain and the zinc-finger-bearing C-terminal region of these regulatory proteins are engaged in oligomerization and DNA binding, respectively. These properties of the Ros/MucR proteins are similar to those of xenogeneic silencers, such as H-NS, MvaT, and Lsr2, which are mainly found in other lineages. In fact, a novel functional model recently proposed for this protein family suggests that they act as H-NS-‘like’ gene silencers. The prokaryotic zinc-finger domain exhibits interesting structural and functional features that are different from that of its eukaryotic counterpart (a βββα topology), as it folds in a significantly larger zinc-binding globular domain (a βββαα topology). Phylogenetic analysis of Ros/MucR homologs suggests an ancestral origin of this type of protein in α-Proteobacteria. Furthermore, multiple duplications and lateral gene transfer events contributing to the diversity and phyletic distribution of these regulatory proteins were found in bacterial genomes. Full article

(This article belongs to the Special Issue Protein and DNA Interaction)

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