E-Mail Alert

Add your e-mail address to receive forthcoming issues of this journal:

Journal Browser

Journal Browser

Special Issue "Protein-DNA Interactions: From Biophysics to Genomics"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: 31 December 2018

Special Issue Editor

Guest Editor
Prof. Junji Iwahara

Department of Biochemistry and Molecular Biology, Sealy Center for Structural Biology and Molecular Biophyiscs, University of Texas Medical Branch, Galveston, Texas, United States
Website | E-Mail
Interests: protein-DNA interactions; transcription factors; dynamics; kinetics; biophysical chemistry; spectroscopy

Special Issue Information

Dear Colleagues,

Protein-DNA interactions are vital for gene regulation, replication, and repair. These essential cellular processes result from a complex action of systems involving various proteins such as transcription factors and DNA repair/modifying enzymes. Many mechanistic aspects of these proteins should be delineated to understand how genes are regulated and maintained. Such knowledge is important, particularly because many human diseases are related to abnormalities in protein-DNA interactions. Adverse effects may be caused by mutations in the genes and cis-regulatory elements, by alteration in post-translational modifications of transcription factors and DNA repair/modifying enzymes, and by epigenetic modifications of DNA and histones. In many cases, these are related to each other in complex networks of molecular interplays. This special issue is intended for providing 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.

Prof. Junji Iwahara
Guest Editor

Manuscript Submission Information

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 papers will be 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. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). 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

  • Biochemistry/biophysics of protein-DNA interactions
  • Chromatin biology
  • DNA repair
  • Epigenetics
  • Gene regulation
  • Genetic regulatory network/circuit
  • Molecular genetics/genomics
  • Protein-DNA dynamics
  • Transcription

Published Papers (9 papers)

View options order results:
result details:
Displaying articles 1-9
Export citation of selected articles as:

Research

Jump to: Review

Open AccessFeature PaperArticle The Amino Acid Composition of Quadruplex Binding Proteins Reveals a Shared Motif and Predicts New Potential Quadruplex Interactors
Molecules 2018, 23(9), 2341; https://doi.org/10.3390/molecules23092341
Received: 27 August 2018 / Revised: 9 September 2018 / Accepted: 12 September 2018 / Published: 13 September 2018
PDF Full-text (2499 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The importance of local DNA structures in the regulation of basic cellular processes is an emerging field of research. Amongst local non-B DNA structures, G-quadruplexes are perhaps the most well-characterized to date, and their presence has been demonstrated in many genomes, including that
[...] Read more.
The importance of local DNA structures in the regulation of basic cellular processes is an emerging field of research. Amongst local non-B DNA structures, G-quadruplexes are perhaps the most well-characterized to date, and their presence has been demonstrated in many genomes, including that of humans. G-quadruplexes are selectively bound by many regulatory proteins. In this paper, we have analyzed the amino acid composition of all seventy-seven described G-quadruplex binding proteins of Homo sapiens. Our comparison with amino acid frequencies in all human proteins and specific protein subsets (e.g., all nucleic acid binding) revealed unique features of quadruplex binding proteins, with prominent enrichment for glycine (G) and arginine (R). Cluster analysis with bootstrap resampling shows similarities and differences in amino acid composition of particular quadruplex binding proteins. Interestingly, we found that all characterized G-quadruplex binding proteins share a 20 amino acid long motif/domain (RGRGR GRGGG SGGSG GRGRG) which is similar to the previously described RG-rich domain (RRGDG RRRGG GGRGQ GGRGR GGGFKG) of the FRM1 G-quadruplex binding protein. Based on this protein fingerprint, we have predicted a new set of potential G-quadruplex binding proteins sharing this interesting domain rich in glycine and arginine residues. Full article
(This article belongs to the Special Issue Protein-DNA Interactions: From Biophysics to Genomics)
Figures

Figure 1

Open AccessArticle Kinetic Features of 3′-5′ Exonuclease Activity of Human AP-Endonuclease APE1
Molecules 2018, 23(9), 2101; https://doi.org/10.3390/molecules23092101
Received: 19 July 2018 / Revised: 2 August 2018 / Accepted: 16 August 2018 / Published: 21 August 2018
PDF Full-text (2867 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Human apurinic/apyrimidinic (AP)-endonuclease APE1 is one of the key enzymes taking part in the repair of damage to DNA. The primary role of APE1 is the initiation of the repair of AP-sites by catalyzing the hydrolytic incision of the phosphodiester bond immediately 5′
[...] Read more.
Human apurinic/apyrimidinic (AP)-endonuclease APE1 is one of the key enzymes taking part in the repair of damage to DNA. The primary role of APE1 is the initiation of the repair of AP-sites by catalyzing the hydrolytic incision of the phosphodiester bond immediately 5′ to the damage. In addition to the AP-endonuclease activity, APE1 possesses 3′-5′ exonuclease activity, which presumably is responsible for cleaning up nonconventional 3′ ends that were generated as a result of DNA damage or as transition intermediates in DNA repair pathways. In this study, the kinetic mechanism of 3′-end nucleotide removal in the 3′-5′ exonuclease process catalyzed by APE1 was investigated under pre-steady-state conditions. DNA substrates were duplexes of deoxyribonucleotides with one 5′ dangling end and it contained a fluorescent 2-aminopurine residue at the 1st, 2nd, 4th, or 6th position from the 3′ end of the short oligonucleotide. The impact of the 3′-end nucleotide, which contained mismatched, undamaged bases or modified bases as well as an abasic site or phosphate group, on the efficiency of 3′-5′ exonuclease activity was determined. Kinetic data revealed that the rate-limiting step of 3′ nucleotide removal by APE1 in the 3′-5′ exonuclease process is the release of the detached nucleotide from the enzyme’s active site. Full article
(This article belongs to the Special Issue Protein-DNA Interactions: From Biophysics to Genomics)
Figures

Figure 1

Open AccessArticle Kinetic Basis of the Bifunctionality of SsoII DNA Methyltransferase
Molecules 2018, 23(5), 1192; https://doi.org/10.3390/molecules23051192
Received: 6 April 2018 / Revised: 4 May 2018 / Accepted: 8 May 2018 / Published: 16 May 2018
PDF Full-text (4239 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Type II restriction–modification (RM) systems are the most widespread bacterial antiviral defence mechanisms. DNA methyltransferase SsoII (M.SsoII) from a Type II RM system SsoII regulates transcription in its own RM system in addition to the methylation function. DNA with a so-called regulatory site
[...] Read more.
Type II restriction–modification (RM) systems are the most widespread bacterial antiviral defence mechanisms. DNA methyltransferase SsoII (M.SsoII) from a Type II RM system SsoII regulates transcription in its own RM system in addition to the methylation function. DNA with a so-called regulatory site inhibits the M.SsoII methylation activity. Using circular permutation assay, we show that M.SsoII monomer induces DNA bending of 31° at the methylation site and 46° at the regulatory site. In the M.SsoII dimer bound to the regulatory site, both protein subunits make equal contributions to the DNA bending, and both angles are in the same plane. Fluorescence of TAMRA, 2-aminopurine, and Trp was used to monitor conformational dynamics of DNA and M.SsoII under pre-steady-state conditions by stopped-flow technique. Kinetic data indicate that M.SsoII prefers the regulatory site to the methylation site at the step of initial protein–DNA complex formation. Nevertheless, in the presence of S-adenosyl-l-methionine, the induced fit is accelerated in the M.SsoII complex with the methylation site, ensuring efficient formation of the catalytically competent complex. The presence of S-adenosyl-l-methionine and large amount of the methylation sites promote efficient DNA methylation by M.SsoII despite the inhibitory effect of the regulatory site. Full article
(This article belongs to the Special Issue Protein-DNA Interactions: From Biophysics to Genomics)
Figures

Graphical abstract

Review

Jump to: Research

Open AccessReview Reading More than Histones: The Prevalence of Nucleic Acid Binding among Reader Domains
Molecules 2018, 23(10), 2614; https://doi.org/10.3390/molecules23102614
Received: 1 September 2018 / Revised: 2 October 2018 / Accepted: 7 October 2018 / Published: 12 October 2018
PDF Full-text (6569 KB) | HTML Full-text | XML Full-text
Abstract
The eukaryotic genome is packaged into the cell nucleus in the form of chromatin, a complex of genomic DNA and histone proteins. Chromatin structure regulation is critical for all DNA templated processes and involves, among many things, extensive post-translational modification of the histone
[...] Read more.
The eukaryotic genome is packaged into the cell nucleus in the form of chromatin, a complex of genomic DNA and histone proteins. Chromatin structure regulation is critical for all DNA templated processes and involves, among many things, extensive post-translational modification of the histone proteins. These modifications can be “read out” by histone binding subdomains known as histone reader domains. A large number of reader domains have been identified and found to selectively recognize an array of histone post-translational modifications in order to target, retain, or regulate chromatin-modifying and remodeling complexes at their substrates. Interestingly, an increasing number of these histone reader domains are being identified as also harboring nucleic acid binding activity. In this review, we present a summary of the histone reader domains currently known to bind nucleic acids, with a focus on the molecular mechanisms of binding and the interplay between DNA and histone recognition. Additionally, we highlight the functional implications of nucleic acid binding in chromatin association and regulation. We propose that nucleic acid binding is as functionally important as histone binding, and that a significant portion of the as yet untested reader domains will emerge to have nucleic acid binding capabilities. Full article
(This article belongs to the Special Issue Protein-DNA Interactions: From Biophysics to Genomics)
Figures

Figure 1

Open AccessFeature PaperReview Zinc Finger Readers of Methylated DNA
Molecules 2018, 23(10), 2555; https://doi.org/10.3390/molecules23102555
Received: 14 September 2018 / Revised: 3 October 2018 / Accepted: 5 October 2018 / Published: 7 October 2018
PDF Full-text (1817 KB) | HTML Full-text | XML Full-text
Abstract
DNA methylation is a prevalent epigenetic modification involved in regulating a number of essential cellular processes, including genomic accessibility and transcriptional outcomes. As such, aberrant alterations in global DNA methylation patterns have been associated with a growing number of disease conditions. Nevertheless, the
[...] Read more.
DNA methylation is a prevalent epigenetic modification involved in regulating a number of essential cellular processes, including genomic accessibility and transcriptional outcomes. As such, aberrant alterations in global DNA methylation patterns have been associated with a growing number of disease conditions. Nevertheless, the full mechanisms by which DNA methylation information is interpreted and translated into genomic responses is not yet fully understood. Methyl-CpG binding proteins (MBPs) function as important mediators of this essential process by selectively reading DNA methylation signals and translating this information into down-stream cellular outcomes. The Cys2His2 zinc finger scaffold is one of the most abundant DNA binding motifs found within human transcription factors, yet only a few zinc finger containing proteins capable of conferring selectivity for mCpG over CpG sites have been characterized. This review summarizes our current structural understanding for the mechanisms by which the zinc finger MBPs evaluated to date read this essential epigenetic mark. Further, some of the biological implications for mCpG readout elicited by this family of MBPs are discussed. Full article
(This article belongs to the Special Issue Protein-DNA Interactions: From Biophysics to Genomics)
Figures

Graphical abstract

Open AccessFeature PaperReview Mechanisms of Protein Search for Targets on DNA: Theoretical Insights
Molecules 2018, 23(9), 2106; https://doi.org/10.3390/molecules23092106
Received: 30 July 2018 / Revised: 13 August 2018 / Accepted: 17 August 2018 / Published: 22 August 2018
PDF Full-text (1210 KB) | HTML Full-text | XML Full-text
Abstract
Protein-DNA interactions are critical for the successful functioning of all natural systems. The key role in these interactions is played by processes of protein search for specific sites on DNA. Although it has been studied for many years, only recently microscopic aspects of
[...] Read more.
Protein-DNA interactions are critical for the successful functioning of all natural systems. The key role in these interactions is played by processes of protein search for specific sites on DNA. Although it has been studied for many years, only recently microscopic aspects of these processes became more clear. In this work, we present a review on current theoretical understanding of the molecular mechanisms of the protein target search. A comprehensive discrete-state stochastic method to explain the dynamics of the protein search phenomena is introduced and explained. Our theoretical approach utilizes a first-passage analysis and it takes into account the most relevant physical-chemical processes. It is able to describe many fascinating features of the protein search, including unusually high effective association rates, high selectivity and specificity, and the robustness in the presence of crowders and sequence heterogeneity. Full article
(This article belongs to the Special Issue Protein-DNA Interactions: From Biophysics to Genomics)
Figures

Figure 1

Open AccessFeature PaperReview Next-Generation Drugs and Probes for Chromatin Biology: From Targeted Protein Degradation to Phase Separation
Molecules 2018, 23(8), 1958; https://doi.org/10.3390/molecules23081958
Received: 17 July 2018 / Revised: 1 August 2018 / Accepted: 1 August 2018 / Published: 6 August 2018
PDF Full-text (3298 KB) | HTML Full-text | XML Full-text
Abstract
Chromatin regulation is a critical aspect of nuclear function. Recent advances have provided detailed information about dynamic three-dimensional organization of chromatin and its regulatory factors. Mechanisms crucial for normal nuclear function and epigenetic control include compartmentalization of biochemical reactions by liquid-phase separated condensates
[...] Read more.
Chromatin regulation is a critical aspect of nuclear function. Recent advances have provided detailed information about dynamic three-dimensional organization of chromatin and its regulatory factors. Mechanisms crucial for normal nuclear function and epigenetic control include compartmentalization of biochemical reactions by liquid-phase separated condensates and signal-dependent regulation of protein stability. Synthetic control of these phenomena by small molecules provides deep insight into essential activities such as histone modification, BAF (SWI/SNF) and PBAF remodeling, Polycomb repression, enhancer looping by cohesin and CTCF, as well as many other processes that contribute to transcription. As a result, a complete understanding of the spatiotemporal mechanisms that underlie chromatin regulation increasingly requires the use of fast-acting drugs and chemical probes. Here, we provide a comprehensive review of next-generation chemical biology tools to interrogate the chromatin regulatory landscape, including selective PROTAC E3 ubiquitin ligase degraders, degrons, fluorescent ligands, dimerizers, inhibitors, and other drugs. These small molecules provide important insights into the mechanisms that govern gene regulation, DNA repair, development, and diseases like cancer. Full article
(This article belongs to the Special Issue Protein-DNA Interactions: From Biophysics to Genomics)
Figures

Graphical abstract

Open AccessReview Pioneer Factors in Animals and Plants—Colonizing Chromatin for Gene Regulation
Molecules 2018, 23(8), 1914; https://doi.org/10.3390/molecules23081914
Received: 9 July 2018 / Revised: 26 July 2018 / Accepted: 28 July 2018 / Published: 31 July 2018
PDF Full-text (949 KB) | HTML Full-text | XML Full-text
Abstract
Unlike most transcription factors (TF), pioneer TFs have a specialized role in binding closed regions of chromatin and initiating the subsequent opening of these regions. Thus, pioneer TFs are key factors in gene regulation with critical roles in developmental transitions, including organ biogenesis,
[...] Read more.
Unlike most transcription factors (TF), pioneer TFs have a specialized role in binding closed regions of chromatin and initiating the subsequent opening of these regions. Thus, pioneer TFs are key factors in gene regulation with critical roles in developmental transitions, including organ biogenesis, tissue development, and cellular differentiation. These developmental events involve some major reprogramming of gene expression patterns, specifically the opening and closing of distinct chromatin regions. Here, we discuss how pioneer TFs are identified using biochemical and genome-wide techniques. What is known about pioneer TFs from animals and plants is reviewed, with a focus on the strategies used by pioneer factors in different organisms. Finally, the different molecular mechanisms pioneer factors used are discussed, highlighting the roles that tertiary and quaternary structures play in nucleosome-compatible DNA-binding. Full article
(This article belongs to the Special Issue Protein-DNA Interactions: From Biophysics to Genomics)
Figures

Graphical abstract

Open AccessReview Recent Advances in Detecting Mitochondrial DNA Heteroplasmic Variations
Molecules 2018, 23(2), 323; https://doi.org/10.3390/molecules23020323
Received: 9 January 2018 / Revised: 27 January 2018 / Accepted: 31 January 2018 / Published: 3 February 2018
PDF Full-text (2430 KB) | HTML Full-text | XML Full-text
Abstract
The co-existence of wild-type and mutated mitochondrial DNA (mtDNA) molecules termed heteroplasmy becomes a research hot point of mitochondria. In this review, we listed several methods of mtDNA heteroplasmy research, including the enrichment of mtDNA and the way of calling heteroplasmic variations. At
[...] Read more.
The co-existence of wild-type and mutated mitochondrial DNA (mtDNA) molecules termed heteroplasmy becomes a research hot point of mitochondria. In this review, we listed several methods of mtDNA heteroplasmy research, including the enrichment of mtDNA and the way of calling heteroplasmic variations. At the present, while calling the novel ultra-low level heteroplasmy, high-throughput sequencing method is dominant while the detection limit of recorded mutations is accurate to 0.01% using the other quantitative approaches. In the future, the studies of mtDNA heteroplasmy may pay more attention to the single-cell level and focus on the linkage of mutations. Full article
(This article belongs to the Special Issue Protein-DNA Interactions: From Biophysics to Genomics)
Figures

Figure 1

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Regulation by bacterial transcription factors: relationship between binding energy and binding site functionality
Author: Marko Djordjevic
Affiliation: Faculty of Biology, University of Belgrade, Studentski Trg 16, 11000 Belgrade, Serbia
Abstract: TF binding sites are relatively short and degenerate motifs, which appear frequently by random in longer stretches of DNA sequence. Such randomly occurring sites with high estimated TF binding energies are often called non-sites, and are considered a major contributor to high number of false positives in bioinformatic (and possibly also experimental) searches of regulatory elements. We recently observed an absence of overrepresentation for sigma70 (bacterial transcription regulator responsible for transcription initiation) binding sites, in genomic regions where transcription initiation signals are abundant. This suggests significant negative selection on non-sites, which might notably reduce their number in genome sequence. We here investigate in detail the extent of such negative selection in different genomic regions, for three pleiotropic bacterial regulators. We find that more accurate energy matrices (describing TF binding specificity) and sequence alignments, lead to a larger extent of underrepresentation, which we interpret in terms of more accurate models being able to better separate between sites and non-sites. We however consistently obtain that while the negative selection is statistically significant, its extent is relatively small, leading to up to 30% reduction in the number of non-sites. We here propose that additional mechanisms may contribute to reduction of TF binding to regions where functional regulation is not expected (e.g., to coding and convergent intergenic regions). In particular our results, based on comparison with genome-wide binding data (ChIP-chip, ChIP-seq), indicate that such regions may be less accessible to TF binding.

Back to Top