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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: closed (31 December 2018).

Special Issue Editor

Prof. Junji Iwahara
E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, Sealy Center for Structural Biology and Molecular Biophyiscs, University of Texas Medical Branch, Galveston, Texas, United States
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

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 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 (15 papers)

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Research

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Open AccessArticle
Endogenous Gene Regulation as a Predicted Main Function of Type I-E CRISPR/Cas System in E. coli
Molecules 2019, 24(4), 784; https://doi.org/10.3390/molecules24040784 - 21 Feb 2019
Cited by 3
Abstract
CRISPR/Cas is an adaptive bacterial immune system, whose CRISPR array can actively change in response to viral infections. However, Type I-E CRISPR/Cas in E. coli (an established model system), appears not to exhibit such active adaptation, which suggests that it might have functions [...] Read more.
CRISPR/Cas is an adaptive bacterial immune system, whose CRISPR array can actively change in response to viral infections. However, Type I-E CRISPR/Cas in E. coli (an established model system), appears not to exhibit such active adaptation, which suggests that it might have functions other than immune response. Through computational analysis, we address the involvement of the system in non-canonical functions. To assess targets of CRISPR spacers, we align them against both E. coli genome and an exhaustive (~230) set of E. coli viruses. We systematically investigate the obtained alignments, such as hit distribution with respect to genome annotation, propensity to target mRNA, the target functional enrichment, conservation of CRISPR spacers and putative targets in related bacterial genomes. We find that CRISPR spacers have a statistically highly significant tendency to target (i) host compared to phage genomes, (ii) one of the two DNA strands, (iii) genomic dsDNA rather than mRNA, (iv) transcriptionally active regions, and (v) sequences (cis-regulatory elements) with slower turn-over rate compared to CRISPR spacers (trans-factors). The results suggest that the Type I-E CRISPR/Cas system has a major role in transcription regulation of endogenous genes, with a potential to rapidly rewire these regulatory interactions, with targets being selected through naïve adaptation. Full article
(This article belongs to the Special Issue Protein-DNA Interactions: From Biophysics to Genomics)
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Open AccessArticle
Effects of Population Dynamics on Establishment of a Restriction-Modification System in a Bacterial Host
Molecules 2019, 24(1), 198; https://doi.org/10.3390/molecules24010198 - 07 Jan 2019
Abstract
In vivo dynamics of protein levels in bacterial cells depend on both intracellular regulation and relevant population dynamics. Such population dynamics effects, e.g., interplay between cell and plasmid division rates, are, however, often neglected in modeling gene expression regulation. Including them in a [...] Read more.
In vivo dynamics of protein levels in bacterial cells depend on both intracellular regulation and relevant population dynamics. Such population dynamics effects, e.g., interplay between cell and plasmid division rates, are, however, often neglected in modeling gene expression regulation. Including them in a model introduces additional parameters shared by the dynamical equations, which can significantly increase dimensionality of the parameter inference. We here analyse the importance of these effects, on a case of bacterial restriction-modification (R-M) system. We redevelop our earlier minimal model of this system gene expression regulation, based on a thermodynamic and dynamic system modeling framework, to include the population dynamics effects. To resolve the problem of effective coupling of the dynamical equations, we propose a “mean-field-like” procedure, which allows determining only part of the parameters at a time, by separately fitting them to expression dynamics data of individual molecular species. We show that including the interplay between kinetics of cell division and plasmid replication is necessary to explain the experimental measurements. Moreover, neglecting population dynamics effects can lead to falsely identifying non-existent regulatory mechanisms. Our results call for advanced methods to reverse-engineer intracellular regulation from dynamical data, which would also take into account the population dynamics effects. Full article
(This article belongs to the Special Issue Protein-DNA Interactions: From Biophysics to Genomics)
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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 - 13 Sep 2018
Cited by 8
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)
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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 - 21 Aug 2018
Cited by 3
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)
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Open AccessArticle
Kinetic Basis of the Bifunctionality of SsoII DNA Methyltransferase
Molecules 2018, 23(5), 1192; https://doi.org/10.3390/molecules23051192 - 16 May 2018
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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Review

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Open AccessReview
Function and Interactions of ERCC1-XPF in DNA Damage Response
Molecules 2018, 23(12), 3205; https://doi.org/10.3390/molecules23123205 - 05 Dec 2018
Cited by 7
Abstract
Numerous proteins are involved in the multiple pathways of the DNA damage response network and play a key role to protect the genome from the wide variety of damages that can occur to DNA. An example of this is the structure-specific endonuclease ERCC1-XPF. [...] Read more.
Numerous proteins are involved in the multiple pathways of the DNA damage response network and play a key role to protect the genome from the wide variety of damages that can occur to DNA. An example of this is the structure-specific endonuclease ERCC1-XPF. This heterodimeric complex is in particular involved in nucleotide excision repair (NER), but also in double strand break repair and interstrand cross-link repair pathways. Here we review the function of ERCC1-XPF in various DNA repair pathways and discuss human disorders associated with ERCC1-XPF deficiency. We also overview our molecular and structural understanding of XPF-ERCC1. Full article
(This article belongs to the Special Issue Protein-DNA Interactions: From Biophysics to Genomics)
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Open AccessReview
Regulation of DNA Double-Strand Break Repair by Non-Coding RNAs
Molecules 2018, 23(11), 2789; https://doi.org/10.3390/molecules23112789 - 27 Oct 2018
Cited by 6
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Protein-DNA Interactions: From Biophysics to Genomics)
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Open AccessFeature PaperReview
Thermodynamic Model for B-Z Transition of DNA Induced by Z-DNA Binding Proteins
Molecules 2018, 23(11), 2748; https://doi.org/10.3390/molecules23112748 - 24 Oct 2018
Cited by 4
Abstract
Z-DNA is stabilized by various Z-DNA binding proteins (ZBPs) that play important roles in RNA editing, innate immune response, and viral infection. In this review, the structural and dynamics of various ZBPs complexed with Z-DNA are summarized to better understand the mechanisms by [...] Read more.
Z-DNA is stabilized by various Z-DNA binding proteins (ZBPs) that play important roles in RNA editing, innate immune response, and viral infection. In this review, the structural and dynamics of various ZBPs complexed with Z-DNA are summarized to better understand the mechanisms by which ZBPs selectively recognize d(CG)-repeat DNA sequences in genomic DNA and efficiently convert them to left-handed Z-DNA to achieve their biological function. The intermolecular interaction of ZBPs with Z-DNA strands is mediated through a single continuous recognition surface which consists of an α3 helix and a β-hairpin. In the ZBP-Z-DNA complexes, three identical, conserved residues (N173, Y177, and W195 in the Zα domain of human ADAR1) play central roles in the interaction with Z-DNA. ZBPs convert a 6-base DNA pair to a Z-form helix via the B-Z transition mechanism in which the ZBP first binds to B-DNA and then shifts the equilibrium from B-DNA to Z-DNA, a conformation that is then selectively stabilized by the additional binding of a second ZBP molecule. During B-Z transition, ZBPs selectively recognize the alternating d(CG)n sequence and convert it to a Z-form helix in long genomic DNA through multiple sequence discrimination steps. In addition, the intermediate complex formed by ZBPs and B-DNA, which is modulated by varying conditions, determines the degree of B-Z transition. Full article
(This article belongs to the Special Issue Protein-DNA Interactions: From Biophysics to Genomics)
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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 - 12 Oct 2018
Cited by 8
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)
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Open AccessFeature PaperReview
Zinc Finger Readers of Methylated DNA
Molecules 2018, 23(10), 2555; https://doi.org/10.3390/molecules23102555 - 07 Oct 2018
Cited by 6
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)
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Open AccessFeature PaperReview
Mechanisms of Protein Search for Targets on DNA: Theoretical Insights
Molecules 2018, 23(9), 2106; https://doi.org/10.3390/molecules23092106 - 22 Aug 2018
Cited by 4
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)
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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 - 06 Aug 2018
Cited by 7
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)
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Open AccessReview
Pioneer Factors in Animals and Plants—Colonizing Chromatin for Gene Regulation
Molecules 2018, 23(8), 1914; https://doi.org/10.3390/molecules23081914 - 31 Jul 2018
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)
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Open AccessReview
Recent Advances in Detecting Mitochondrial DNA Heteroplasmic Variations
Molecules 2018, 23(2), 323; https://doi.org/10.3390/molecules23020323 - 03 Feb 2018
Cited by 6
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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Open AccessFeature PaperCommentary
CENP-A Ubiquitylation Contributes to Maintaining the Chromosomal Location of the Centromere
Molecules 2019, 24(3), 402; https://doi.org/10.3390/molecules24030402 - 22 Jan 2019
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, centromere protein A (CENP-A), in centromeric nucleosomes. However, the precise mechanisms of deposition, maintenance, and inheritance [...] Read more.
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, centromere protein A (CENP-A), in centromeric nucleosomes. However, the precise mechanisms of deposition, maintenance, and inheritance of CENP-A at centromeres are unclear. We have reported that CENP-A deposition requires ubiquitylation of CENP-A lysine 124 mediated by the E3 ligase activity of Cullin 4A (CUL4A)—RING-box protein 1 (RBX1)—COP9 signalsome complex subunit 8 (COPS8). We have proposed a model of inheritance for CENP-A ubiquitylation, through dimerization between rounds of cell divisions, that maintains the position of centromeres. Full article
(This article belongs to the Special Issue Protein-DNA Interactions: From Biophysics to Genomics)
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