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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: 30 August 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 (2 papers)

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Research

Jump to: Review

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
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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)
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Graphical abstract

Review

Jump to: Research

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)
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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.

Type: Review
Title: Regulation of Double-Strand DNA Break Repair By Non-Coding RNAs
Author: Roopa Thapar
Affiliation: Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030.
Abstract: DNA double-strand breaks (DSBs) are deleterious lesions that are generated in response to ionizing radiation or replication fork collapse that can lead to genomic instability and cancer. Eukaryotes have evolved two major pathways, namely homologous recombination (HR) and non-homologous end joining (NHEJ) to repair DSBs. Whereas the roles of protein-DNA interactions in HR and NHEJ have been fairly well defined, the functions of small and long non-coding RNAs and RNA-DNA hybrids in the DNA damage response is just beginning to be elucidated. This review summarizes recent discoveries on the identification of non-coding RNAs and RNA-mediated regulation of DSB repair.

Type: Review
Title: Mechanisms of Protein Search for Targets on DNA: Theoretical Insights
Author: A.A. Shvets, M.A. Kochugaeva and A.B. Kolomeisky
Affiliation: Department of Chemistry-MS60, Rice University, 6100 Main Street, Houston, TX 77005-1892, USA
Abstract: One of the most important phenomena in protein-DNA interactions is the protein search for specific sites on DNA, which starts most major biological processes in living cells. Although it has been studied for many years, only recently some microscopic aspects of this process became more clarified. In this paper, we present a review on our current theoretical understanding of molecular mechanisms of the protein search. We present a comprehensive discrete-state stochastic method to explain main features of the process. Our approach explains many fascinating features of the protein search, including unusually high association rates, high selectivity and specificity, and the robustness of the protein search in the presence of crowders and conformational fluctuations.

Type: Review
Title: Zinc Finger Readers of Methylated DNA
Author: N.O. Hudson and B.A. Buck-Koehntop
Affiliation: Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112-0850, USA
Abstract: DNA methylation is a prevalent epigenetic modification involved in regulating genomic accessibility and subsequent transcriptional outcomes. As such, aberrant alterations in global DNA methylation patterns have been associated with a growing number of diseases, including cancer. Methyl-CpG binding proteins are essential for mediating this important cellular process in that they selectively read DNA methylation signals, translate them into localized chromatin architectural rearrangements and alter transcription responses. This review summarizes our current understanding for the mechanisms by which the zinc finger methyl-CpG binding proteins read and interpret information from this essential epigenetic mark.

Type: Review
Title: Reading more than histones: the prevalence of nucleic acid binding among reader domains
Author: Catherine A. Musselman
Affiliation: Department of Biochemistry, University of Iowa, Iowa City, Iowa, USA
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 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 have been recently identified as also harboring nucleic acid binding function. 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 effect on histone recognition. Additionally, we highlight the functional implications of nucleic acid binding in chromatin targeting and regulation. We propose that nucleic acid binding is common and functionally important, and that a significant portion of the as yet untested domains have these binding capabilities.

Type: Review
Title: B-Z transition mechanism of DNA induced by Z-DNA binding proteins
Author: Ae-Ree Lee, Na-Hyun Kim, and Joon-Hwa Lee
Affiliation: Department of Chemistry and RINS, Gyeongsang National University, Jinju 52828, Korea
Abstract: Z-DNA is induced by various Z-DNA binding proteins (ZBPs) that play important roles in RNA editing, innate immune response, and viral infection. ZBPs convert a 6-base paired DNA duplex to Z-form helix via active B-Z transition mechanism in which the ZBP first binds to B-DNA and then converts it to left-handed Z-DNA, a conformation that is then stabilized by the additional binding of a second ZBP molecule. The intermediate complex formed by ZBPs and B-DNA, which is modulated by varying conditions, determines the degree of B-Z transition. In this intermediate structure of DNA containing CG-repeat as well as AT-rich sequence, the CG-repeat displays longer lifetime for the opening state and the AT-rich region is destabilized to easily form the B-Z junction structure.

Type of paper: Review
Title: From Phase Separation to Protein Degradation: New Epigenetic Drugs and Chemical Probes for Chromatin Biology
Authors: Katerina Cermakova 1 and H. Courtney Hodges 1,2
Affiliation: 1. Department of Molecular & Cellular Biology, Center for Precision Environmental Health, and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
2. Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Abstract: Spatiotemporal chromatin regulation is a critical aspect of nuclear function. Recent technological advances have provided detailed information about three-dimensional organization of chromatin and factors that directly regulate DNA, histones, or other proteins. However, a complete understanding of the spatiotemporal mechanisms that underlie chromatin regulation increasingly requires the use of new drugs and more sophisticated chemical probes. Recently discovered mechanisms that are crucial for normal nuclear function and transcription control include compartmentalization of biochemical reactions by liquid-phase separation, control of chromatin looping, and regulated protein stability. Here we review emerging chemical biology tools instrumental for understanding the mechanisms that govern dynamic regulatory processes on chromatin. These recently developed tools are providing important insights into gene regulation, DNA repair, development, and diseases like cancer.

Type of paper: Review
Title: CENP-A ubiquitylation contributes to maintain the chromosomal location of the centromere
Author: Katsumi Kitagawa
Affiliation: Greehey Children’s Cancer Research Institute, Department of Molecular Medicine, UT Health Science Center San Antonio School of Medicine, Mail Code 7784, 8403 Floyd Curl Dr, San Antonio, TX 78229-3900 USA
Abstract: The centromere plays an essential role in accurate chromosome segregation, and the chromosomal location of the centromere is determined by the presence of a histone H3 variant, CENP-A in centromeric nucleosomes. However, the precise mechanism of deposition, maintenance, and inheritance of CENP-A at centromeres has been unclear. We have reported that CENP-A deposition requires ubiquitylation of CENP-A lysine 124 mediated by the E3 ligase activity of CUL4A -RBX1-COPS8. We have proposed a model of inheritance of CENP-A ubiquitylation, through dimerization between rounds of cell divisions, to maintain the position of centromeres.

Type of paper: Review
Title: Pioneer Transcription Factors in Eukaryotes-Colonising Chromatin for Gene Regulation
Author: Chloe ZUBIETA
Affiliation: CNRS, CEA/BIG/Univ. Grenoble-Alpes/INRA, 17 rue des Martyrs, 38054 Grenoble, CEDEX 9, France
Abstract: Unlike most transcription factors (TF), pioneer TFs have a unique role of binding their cognate DNA motif in closed regions of chromatin. As such, pioneer TFs play a critical role in gene regulation, particularly during developmental transitions such as organ biogenesis or cellular differentiation. These events necessitate major reprogramming of gene expression with the opening and closing of different chromatin regions. Here we discuss how pioneer TFs are able to bind compacted nucleosomal DNA and subsequently open these Regions, rendering them competent for gene expression. The different strategies used by pioneers are examined with a focus on how the tertiary and quaternary structure of the proteins enables them to outcompete histones for DNA-binding sites. Pioneer TFs from animals, yeast and plants are compared underscoring both the common strategies and differences in their mode of function.

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.

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