Feature Papers in Molecular Genetics

A topical collection in Biomolecules (ISSN 2218-273X). This collection belongs to the section "Molecular Genetics".

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Editor

Department of Genetics, Evolution & Environment and Institute of Healthy Ageing, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK
Interests: gene regulation; genomics; transcriptomics; non-coding RNAs; genome function and evolution; fission yeast; cellular quiescence and ageing
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Dear Colleagues,

This Topical Collection, “Feature Papers in Molecular Genetics”, will bring together high-quality research articles, review articles, and communications on all aspects of molecular genetics. It is dedicated to diverse recent advances in genetics research, as highlighted in the topics below, and comprises a selection of exclusive papers from the Editorial Board Members (EBMs) of the Molecular Genetics Section as well as invited papers from relevant experts. We also welcome established experts in the field to make contributions to this Topical Collection. Please note that all invited papers will be published online once accepted. We aim to represent our Section as an attractive open access publishing platform for molecular genetics research.

Topics include, without being limited to:

    Chromosome biology;
    Epigenetics;
    Gene editing and genetic variants;
    Gene regulation and transcriptomics;
    Genetic assays and methods;
    Genetic screens and gene-function analyses;
    Genome function and evolution;
    Genotype-phenotype relationships;
    Medical genetics and disease biology;
    Molecular evolution;
    Non-coding RNAs;
    Population genetics and complex traits;
    Synthetic biology.

Prof. Dr. Jürg Bähler
Collection Editor

Manuscript Submission Information

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Published Papers (16 papers)

2023

Jump to: 2022, 2021

10 pages, 1213 KiB  
Review
ATP12A Proton Pump as an Emerging Therapeutic Target in Cystic Fibrosis and Other Respiratory Diseases
by Michał Dębczyński, Giulia Gorrieri, Damian Mojsak, Floriana Guida, Federico Zara and Paolo Scudieri
Biomolecules 2023, 13(10), 1455; https://doi.org/10.3390/biom13101455 - 27 Sep 2023
Viewed by 1220
Abstract
ATP12A encodes the catalytic subunit of the non-gastric proton pump, which is expressed in many epithelial tissues and mediates the secretion of protons in exchange for potassium ions. In the airways, ATP12A-dependent proton secretion contributes to complex mechanisms regulating the composition and properties [...] Read more.
ATP12A encodes the catalytic subunit of the non-gastric proton pump, which is expressed in many epithelial tissues and mediates the secretion of protons in exchange for potassium ions. In the airways, ATP12A-dependent proton secretion contributes to complex mechanisms regulating the composition and properties of the fluid and mucus lining the respiratory epithelia, which are essential to maintain the airway host defense and the respiratory health. Increased expression and activity of ATP12A in combination with the loss of other balancing activities, such as the bicarbonate secretion mediated by CFTR, leads to excessive acidification of the airway surface liquid and mucus dysfunction, processes that play relevant roles in the pathogenesis of cystic fibrosis and other chronic inflammatory respiratory disorders. In this review, we summarize the findings dealing with ATP12A expression, function, and modulation in the airways, which led to the consideration of ATP12A as a potential therapeutic target for the treatment of cystic fibrosis and other airway diseases; we also highlight the current advances and gaps regarding the development of therapeutic strategies aimed at ATP12A inhibition. Full article
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16 pages, 25164 KiB  
Article
Divergent Pharmacology and Biased Signaling of the Four Melanocortin-4 Receptor Isoforms in Rainbow Trout (Oncorhynchus mykiss)
by Ren-Lei Ji, Ting Liu, Zhi-Shuai Hou, Hai-Shen Wen and Ya-Xiong Tao
Biomolecules 2023, 13(8), 1248; https://doi.org/10.3390/biom13081248 - 16 Aug 2023
Viewed by 913
Abstract
The melanocortin-4 receptor (MC4R) is essential for the modulation of energy balance and reproduction in both fish and mammals. Rainbow trout (Oncorhynchus mykiss) has been extensively studied in various fields and provides a unique opportunity to investigate divergent physiological roles of [...] Read more.
The melanocortin-4 receptor (MC4R) is essential for the modulation of energy balance and reproduction in both fish and mammals. Rainbow trout (Oncorhynchus mykiss) has been extensively studied in various fields and provides a unique opportunity to investigate divergent physiological roles of paralogues. Herein we identified four trout mc4r (mc4ra1, mc4ra2, mc4rb1, and mc4rb2) genes. Four trout Mc4rs (omMc4rs) were homologous to those of teleost and mammalian MC4Rs. Multiple sequence alignments, a phylogenetic tree, chromosomal synteny analyses, and pharmacological studies showed that trout mc4r genes may have undergone different evolutionary processes. All four trout Mc4rs bound to two peptide agonists and elevated intracellular cAMP levels dose-dependently. High basal cAMP levels were observed at two omMc4rs, which were decreased by Agouti-related peptide. Only omMc4rb2 was constitutively active in the ERK1/2 signaling pathway. Ipsen 5i, ML00253764, and MCL0020 were biased allosteric modulators of omMc4rb1 with selective activation upon ERK1/2 signaling. ML00253764 behaved as an allosteric agonist in Gs-cAMP signaling of omMc4rb2. This study will lay the foundation for future physiological studies of various mc4r paralogs and reveal the evolution of MC4R in vertebrates. Full article
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11 pages, 2164 KiB  
Review
From Environmental Epigenetics to the Inheritance of Acquired Traits: A Historian and Molecular Perspective on an Unnecessary Lamarckian Explanation
by Mauro Mandrioli
Biomolecules 2023, 13(7), 1077; https://doi.org/10.3390/biom13071077 - 05 Jul 2023
Cited by 1 | Viewed by 1656
Abstract
In the last decade, it has been suggested that epigenetics may enhance the adaptive possibilities of animals and plants to novel environments and/or habitats and that such epigenetic changes may be inherited from parents to offspring, favoring their adaptation. As a consequence, several [...] Read more.
In the last decade, it has been suggested that epigenetics may enhance the adaptive possibilities of animals and plants to novel environments and/or habitats and that such epigenetic changes may be inherited from parents to offspring, favoring their adaptation. As a consequence, several Authors called for a shift in the Darwinian paradigm, asking for a neo-Lamarckian view of evolution. Regardless of what will be discovered about the mechanisms of rapid adaptation to environmental changes, the description of epigenetic inheritance as a Lamarckian process is incorrect from a historical point of view and useless at a scientific level. At the same time, even if some examples support the presence of adaptation without the involvement of changes in DNA sequences, in the current scenario no revolution is actually occurring, so we are simply working on a stimulating research program that needs to be developed but that is, at present, completely Darwinian. Full article
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10 pages, 1591 KiB  
Communication
Lnc-uc.147 Is Associated with Disease Stage of Liver, Gastric, and Renal Cancer
by Ana Carolina Rodrigues, Erika Pereira Zambalde, Daniel de Lima Bellan, Edvaldo da Silva Trindade, Enilze Maria de Souza Fonseca Ribeiro, George Calin, Daniela Fiori Gradia and Jaqueline Carvalho de Oliveira
Biomolecules 2023, 13(2), 265; https://doi.org/10.3390/biom13020265 - 31 Jan 2023
Cited by 1 | Viewed by 1700
Abstract
Lnc-uc.147, a long non-coding RNA derived from a transcribed ultraconserved region (T-UCR), was previously evidenced in breast cancer. However, the role of this region in other tumor types was not previously investigated. The present study aimed to investigate lnc-uc.147 in different types of [...] Read more.
Lnc-uc.147, a long non-coding RNA derived from a transcribed ultraconserved region (T-UCR), was previously evidenced in breast cancer. However, the role of this region in other tumor types was not previously investigated. The present study aimed to investigate lnc-uc.147 in different types of cancer, as well as to suggest lnc-uc.147 functional and regulation aspects. From solid tumor datasets analysis of The Cancer Genome Atlas (TCGA), deregulated lnc-uc.147 expression was associated with the histologic grade of hepatocellular carcinoma, and with the tumor stage of clear cell renal and gastric adenocarcinoma. Considering the epidemiologic relevance of liver cancer, silencing lnc-uc.147 reduced the viability and clonogenic capacity of HepG2 cell lines. Additionally, we suggest a relation between the transcription factor TEAD4 and lnc-uc.147 in liver and breast cancer cells. Full article
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2022

Jump to: 2023, 2021

18 pages, 3842 KiB  
Article
Modulation of Canine Melanocortin-3 and -4 Receptors by Melanocortin-2 Receptor Accessory Protein 1 and 2
by Ren-Lei Ji, Shan-Shan Jiang and Ya-Xiong Tao
Biomolecules 2022, 12(11), 1608; https://doi.org/10.3390/biom12111608 - 01 Nov 2022
Cited by 1 | Viewed by 2004
Abstract
The neural melanocortin receptors (MCRs), melanocortin-3 and -4 receptors (MC3R and MC4R), have crucial roles in regulating energy homeostasis. The melanocortin-2 receptor accessory proteins (MRAPs, MRAP1 and MRAP2) have been shown to regulate neural MCRs in a species-specific manner. The potential effects of [...] Read more.
The neural melanocortin receptors (MCRs), melanocortin-3 and -4 receptors (MC3R and MC4R), have crucial roles in regulating energy homeostasis. The melanocortin-2 receptor accessory proteins (MRAPs, MRAP1 and MRAP2) have been shown to regulate neural MCRs in a species-specific manner. The potential effects of MRAP1 and MRAP2 on canine neural MCRs have not been investigated before. Herein, we cloned canine (c) MC3R and identified one canine MRAP2 splice variant, MRAP2b, with N-terminal extension of cMRAP2a. Canine MC3R showed higher maximal responses to five agonists than those of human MC3R. We further investigated the modulation of cMRAP1, cMRAP2a, and cMRAP2b, on cMC3R and cMC4R pharmacology. For the cMC3R, all MRAPs had no effect on trafficking; cMRAP1 significantly decreased Bmax whereas cMRAP2a and cMRAP2b significantly increased Bmax. Both MRAP1 and MRAP2a decreased Rmaxs in response to α-MSH and ACTH; MRAP2b only decreased α-MSH-stimulated cAMP generation. For the MC4R, MRAP1 and MRAP2a increased cell surface expression, and MRAP1 and MRAP2a increased Bmaxs. All MRAPs had increased affinities to α-MSH and ACTH. MRAP2a increased ACTH-induced cAMP levels, whereas MRAP2b decreased α-MSH- and ACTH-stimulated cAMP production. These findings may lead to a better understanding of the regulation of neural MCRs by MRAP1 and MRAP2s. Full article
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15 pages, 1541 KiB  
Review
An Overview of Molecular Mechanisms in Fabry Disease
by Federica Amodio, Martina Caiazza, Emanuele Monda, Marta Rubino, Laura Capodicasa, Flavia Chiosi, Vincenzo Simonelli, Francesca Dongiglio, Fabio Fimiani, Nicola Pepe, Cristina Chimenti, Paolo Calabrò and Giuseppe Limongelli
Biomolecules 2022, 12(10), 1460; https://doi.org/10.3390/biom12101460 - 12 Oct 2022
Cited by 5 | Viewed by 3949
Abstract
Fabry disease (FD) (OMIM #301500) is a rare genetic lysosomal storage disorder (LSD). LSDs are characterized by inappropriate lipid accumulation in lysosomes due to specific enzyme deficiencies. In FD, the defective enzyme is α-galactosidase A (α-Gal A), which is due to a mutation [...] Read more.
Fabry disease (FD) (OMIM #301500) is a rare genetic lysosomal storage disorder (LSD). LSDs are characterized by inappropriate lipid accumulation in lysosomes due to specific enzyme deficiencies. In FD, the defective enzyme is α-galactosidase A (α-Gal A), which is due to a mutation in the GLA gene on the X chromosome. The enzyme deficiency leads to a continuous deposition of neutral glycosphingolipids (globotriaosylceramide) in the lysosomes of numerous tissues and organs, including endothelial cells, smooth muscle cells, corneal epithelial cells, renal glomeruli and tubules, cardiac muscle and ganglion cells of the nervous system. This condition leads to progressive organ failure and premature death. The increasing understanding of FD, and LSD in general, has led in recent years to the introduction of enzyme replacement therapy (ERT), which aims to slow, if not halt, the progression of the metabolic disorder. In this review, we provide an overview of the main features of FD, focusing on its molecular mechanism and the role of biomarkers. Full article
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12 pages, 2039 KiB  
Article
Human Melanocortin-2 Receptor: Identifying a Role for Residues in the TM4, EC2, and TM5 Domains in Activation and Trafficking as a Result of Co-Expression with the Accessory Protein, Mrap1 in Chinese Hamster Ovary Cells
by Perry V. Davis, Ciaran A. Shaughnessy and Robert M. Dores
Biomolecules 2022, 12(10), 1422; https://doi.org/10.3390/biom12101422 - 04 Oct 2022
Cited by 4 | Viewed by 1323
Abstract
Human melanocortin-2 receptor (hMC2R) co-expressed with the accessory protein mouse (m)MRAP1 in Chinese Hamster Ovary (CHO) cells has been used as a model system to investigate the activation and trafficking of hMC2R. A previous study had shown that the N-terminal domain of mMRAP1 [...] Read more.
Human melanocortin-2 receptor (hMC2R) co-expressed with the accessory protein mouse (m)MRAP1 in Chinese Hamster Ovary (CHO) cells has been used as a model system to investigate the activation and trafficking of hMC2R. A previous study had shown that the N-terminal domain of mMRAP1 makes contact with one of the extracellular domains of hMC2R to facilitate activation of hMC2R. A chimeric receptor paradigm was used in which the extracellular domains of hMC2R were replaced with the corresponding domains from Xenopus tropicalis MC1R, a receptor that does not interact with MRAP1, to reveal that EC2 (Extracellular domain 2) is the most likely contact site for hMC2R and mMRAP1 to facilitate activation of the receptor following an ACTH binding event. Prior to activation, mMRAP1 facilitates the trafficking of hMC2R from the ER to the plasma membrane. This process is dependent on the transmembrane domain (TM) of mMRAP1 making contact with one or more TMs of hMC2R. A single alanine substitution paradigm was used to identify residues in TM4 (i.e., I163, M165), EC2 (F167), and TM5 (F178) that play a role in the trafficking of hMC2R to the plasma membrane. These results provide further clarification of the activation mechanism for hMC2R. Full article
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8 pages, 1109 KiB  
Communication
Use of Bacterial Extracellular Vesicles for Gene Delivery to Host Cells
by Su-Im Kim, Jae Yeong Ha, Song-Yi Choi, Su-Hyung Hong and Heon-Jin Lee
Biomolecules 2022, 12(9), 1171; https://doi.org/10.3390/biom12091171 - 24 Aug 2022
Cited by 3 | Viewed by 2184
Abstract
Extracellular vesicles (EVs), which are nanosized membranous particles secreted from both prokaryotic and eukaryotic cells, can deliver various biological molecules, such as nucleic acids, proteins, and lipids, into recipient cells. However, contrary to what is known about eukaryotic EVs, whether bacterial EVs (bEVs) [...] Read more.
Extracellular vesicles (EVs), which are nanosized membranous particles secreted from both prokaryotic and eukaryotic cells, can deliver various biological molecules, such as nucleic acids, proteins, and lipids, into recipient cells. However, contrary to what is known about eukaryotic EVs, whether bacterial EVs (bEVs) can be used as transporters for bioactive molecules is becoming a hot area of research. In this study, we electroporated enhanced green fluorescent protein (EGFP) genes and precursor microRNA of Cel-miR-39 (pre-Cel-miR-39) from isolated bEVs of Escherichia coli and Lactobacillus reuteri. The EGFP plasmid, synthetic EGFP RNA, and pre-Cel-miR-39 were successfully delivered into the murine microglial BV2 cells via bEVs. PCR and confocal microscopy analysis confirmed the transfer of the EGFP plasmid and RNA. The bEV-delivered exogenous pre-Cel-miR-39 was further processed into the mature form of Cel-miR-39; its incorporation into Ago2—a major component of the RNA-induced silencing complex—was assessed using RNA-immunoprecipitation–PCR. Taken together, bEVs can be used as vehicles to deliver genetic materials and for novel biotechnological applications, such as gene transfer and mRNA vaccines. Full article
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15 pages, 810 KiB  
Review
Cutting-Edge AI Technologies Meet Precision Medicine to Improve Cancer Care
by Peng-Chan Lin, Yi-Shan Tsai, Yu-Min Yeh and Meng-Ru Shen
Biomolecules 2022, 12(8), 1133; https://doi.org/10.3390/biom12081133 - 17 Aug 2022
Cited by 3 | Viewed by 3003
Abstract
To provide precision medicine for better cancer care, researchers must work on clinical patient data, such as electronic medical records, physiological measurements, biochemistry, computerized tomography scans, digital pathology, and the genetic landscape of cancer tissue. To interpret big biodata in cancer genomics, an [...] Read more.
To provide precision medicine for better cancer care, researchers must work on clinical patient data, such as electronic medical records, physiological measurements, biochemistry, computerized tomography scans, digital pathology, and the genetic landscape of cancer tissue. To interpret big biodata in cancer genomics, an operational flow based on artificial intelligence (AI) models and medical management platforms with high-performance computing must be set up for precision cancer genomics in clinical practice. To work in the fast-evolving fields of patient care, clinical diagnostics, and therapeutic services, clinicians must understand the fundamentals of the AI tool approach. Therefore, the present article covers the following four themes: (i) computational prediction of pathogenic variants of cancer susceptibility genes; (ii) AI model for mutational analysis; (iii) single-cell genomics and computational biology; (iv) text mining for identifying gene targets in cancer; and (v) the NVIDIA graphics processing units, DRAGEN field programmable gate arrays systems and AI medical cloud platforms in clinical next-generation sequencing laboratories. Based on AI medical platforms and visualization, large amounts of clinical biodata can be rapidly copied and understood using an AI pipeline. The use of innovative AI technologies can deliver more accurate and rapid cancer therapy targets. Full article
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9 pages, 1067 KiB  
Article
MTHFR SNPs (Methyl Tetrahydrofolate Reductase, Single Nucleotide Polymorphisms) C677T and A1298C Prevalence and Serum Homocysteine Levels in >2100 Hypofertile Caucasian Male Patients
by Arthur Clément, Edouard Amar, Charles Brami, Patrice Clément, Silvia Alvarez, Laetitia Jacquesson-Fournols, Céline Davy, Marc Lalau-Keraly and Yves Menezo
Biomolecules 2022, 12(8), 1086; https://doi.org/10.3390/biom12081086 - 07 Aug 2022
Cited by 4 | Viewed by 2558
Abstract
Methylation is a crucially important ubiquitous biochemical process, which covalently adds methyl groups to a variety of molecular targets. It is the key regulatory process that determines the acquisition of imprinting and epigenetic marks during gametogenesis. Methylation processes are dependent upon two metabolic [...] Read more.
Methylation is a crucially important ubiquitous biochemical process, which covalently adds methyl groups to a variety of molecular targets. It is the key regulatory process that determines the acquisition of imprinting and epigenetic marks during gametogenesis. Methylation processes are dependent upon two metabolic cycles, the folates and the one-carbon cycles. The activity of these two cycles is compromised by single nucleotide polymorphisms (SNPs) in the gene encoding the Methylenetetrahydrofolate reductase (MTHFR) enzyme. These SNPs affect spermatogenesis and oocyte maturation, creating cytologic/chromosomal anomalies. The two main MTHFR SNP variants C677T (c.6777C>T) and A1298C (c.1298A>C) together with serum homocysteine levels were tested in men with >3 years’ duration of infertility who had failed several ART attempts with the same partner. These patients are often classified as having “idiopathic infertility”. We observed that the genetic status with highest prevalence in this group is the heterozygous C677T, followed by the combined heterozygous C677T/A1298C, and then A1298C; these three variants represent 65% of our population. Only 13.1% of the patients tested are wild type (WT), C677C/A1298A). The homozygous 677TT and the combined heterozygote 677CT/1298AC groups have the highest percentage of patients with an elevated circulating homocysteine level of >15 µMolar (57.8% and 18.8%, respectively, which is highly significant for both). Elevated homocysteine is known to be detrimental to spermatogenesis, and the population with this parameter is not marginal. In conclusion, determination of these two SNPs and serum homocysteine should not be overlooked for patients with severe infertility of long duration, including those with repeated miscarriages. Patients must also be informed about pleiotropic medical implications relevant to their own health, as well as to the health of future children. Full article
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20 pages, 1457 KiB  
Review
Spatiotemporal Coupling of DNA Supercoiling and Genomic Sequence Organization—A Timing Chain for the Bacterial Growth Cycle?
by Georgi Muskhelishvili, Patrick Sobetzko and Andrew Travers
Biomolecules 2022, 12(6), 831; https://doi.org/10.3390/biom12060831 - 15 Jun 2022
Cited by 3 | Viewed by 2089
Abstract
In this article we describe the bacterial growth cycle as a closed, self-reproducing, or autopoietic circuit, reestablishing the physiological state of stationary cells initially inoculated in the growth medium. In batch culture, this process of self-reproduction is associated with the gradual decline in [...] Read more.
In this article we describe the bacterial growth cycle as a closed, self-reproducing, or autopoietic circuit, reestablishing the physiological state of stationary cells initially inoculated in the growth medium. In batch culture, this process of self-reproduction is associated with the gradual decline in available metabolic energy and corresponding change in the physiological state of the population as a function of “travelled distance” along the autopoietic path. We argue that this directional alteration of cell physiology is both reflected in and supported by sequential gene expression along the chromosomal OriC-Ter axis. We propose that during the E. coli growth cycle, the spatiotemporal order of gene expression is established by coupling the temporal gradient of supercoiling energy to the spatial gradient of DNA thermodynamic stability along the chromosomal OriC-Ter axis. Full article
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19 pages, 3710 KiB  
Article
CAPTURE of the Human U2 snRNA Genes Expands the Repertoire of Associated Factors
by Joana Guiro, Mathias Fagbemi, Michael Tellier, Justyna Zaborowska, Stephanie Barker, Marjorie Fournier and Shona Murphy
Biomolecules 2022, 12(5), 704; https://doi.org/10.3390/biom12050704 - 14 May 2022
Cited by 1 | Viewed by 2971
Abstract
In order to identify factors involved in transcription of human snRNA genes and 3′ end processing of the transcripts, we have carried out CRISPR affinity purification in situ of regulatory elements (CAPTURE), which is deadCas9-mediated pull-down, of the tandemly repeated U2 snRNA genes [...] Read more.
In order to identify factors involved in transcription of human snRNA genes and 3′ end processing of the transcripts, we have carried out CRISPR affinity purification in situ of regulatory elements (CAPTURE), which is deadCas9-mediated pull-down, of the tandemly repeated U2 snRNA genes in human cells. CAPTURE enriched many factors expected to be associated with these human snRNA genes including RNA polymerase II (pol II), Cyclin-Dependent Kinase 7 (CDK7), Negative Elongation Factor (NELF), Suppressor of Ty 5 (SPT5), Mediator 23 (MED23) and several subunits of the Integrator Complex. Suppressor of Ty 6 (SPT6); Cyclin K, the partner of Cyclin-Dependent Kinase 12 (CDK12) and Cyclin-Dependent Kinase 13 (CDK13); and SWI/SNF chromatin remodelling complex-associated SWI/SNF-related, Matrix-associated, Regulator of Chromatin (SMRC) factors were also enriched. Several polyadenylation factors, including Cleavage and Polyadenylation Specificity Factor 1 (CPSF1), Cleavage Stimulation Factors 1 and 2 (CSTF1,and CSTF2) were enriched by U2 gene CAPTURE. We have already shown by chromatin immunoprecipitation (ChIP) that CSTF2—and Pcf11 and Ssu72, which are also polyadenylation factors—are associated with the human U1 and U2 genes. ChIP-seq and ChIP-qPCR confirm the association of SPT6, Cyclin K, and CDK12 with the U2 genes. In addition, knockdown of SPT6 causes loss of subunit 3 of the Integrator Complex (INTS3) from the U2 genes, indicating a functional role in snRNA gene expression. CAPTURE has therefore expanded the repertoire of transcription and RNA processing factors associated with these genes and helped to identify a functional role for SPT6. Full article
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26 pages, 6801 KiB  
Review
PrimPol: A Breakthrough among DNA Replication Enzymes and a Potential New Target for Cancer Therapy
by Alberto Díaz-Talavera, Cristina Montero-Conde, Luis Javier Leandro-García and Mercedes Robledo
Biomolecules 2022, 12(2), 248; https://doi.org/10.3390/biom12020248 - 03 Feb 2022
Cited by 5 | Viewed by 4230 | Correction
Abstract
DNA replication can encounter blocking obstacles, leading to replication stress and genome instability. There are several mechanisms for evading this blockade. One mechanism consists of repriming ahead of the obstacles, creating a new starting point; in humans, PrimPol is responsible for carrying out [...] Read more.
DNA replication can encounter blocking obstacles, leading to replication stress and genome instability. There are several mechanisms for evading this blockade. One mechanism consists of repriming ahead of the obstacles, creating a new starting point; in humans, PrimPol is responsible for carrying out this task. PrimPol is a primase that operates in both the nucleus and mitochondria. In contrast with conventional primases, PrimPol is a DNA primase able to initiate DNA synthesis de novo using deoxynucleotides, discriminating against ribonucleotides. In vitro, PrimPol can act as a DNA primase, elongating primers that PrimPol itself sythesizes, or as translesion synthesis (TLS) DNA polymerase, elongating pre-existing primers across lesions. However, the lack of evidence for PrimPol polymerase activity in vivo suggests that PrimPol only acts as a DNA primase. Here, we provide a comprehensive review of human PrimPol covering its biochemical properties and structure, in vivo function and regulation, and the processes that take place to fill the gap-containing lesion that PrimPol leaves behind. Finally, we explore the available data on human PrimPol expression in different tissues in physiological conditions and its role in cancer. Full article
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14 pages, 2591 KiB  
Article
Regulation of Melanocortin-3 and -4 Receptors by Isoforms of Melanocortin-2 Receptor Accessory Protein 1 and 2
by Ren-Lei Ji and Ya-Xiong Tao
Biomolecules 2022, 12(2), 244; https://doi.org/10.3390/biom12020244 - 02 Feb 2022
Cited by 6 | Viewed by 2550
Abstract
The neural melanocortin receptors (MCRs), melanocortin-3 and -4 receptors (MC3R and MC4R), play essential non-redundant roles in the regulation of energy homeostasis. Interaction of neural MCRs and melanocortin-2 receptor accessory proteins (MRAPs, MRAP1 and MRAP2) is suggested to play pivotal roles in MC3R [...] Read more.
The neural melanocortin receptors (MCRs), melanocortin-3 and -4 receptors (MC3R and MC4R), play essential non-redundant roles in the regulation of energy homeostasis. Interaction of neural MCRs and melanocortin-2 receptor accessory proteins (MRAPs, MRAP1 and MRAP2) is suggested to play pivotal roles in MC3R and MC4R signaling. In the present study, we identified two new human (h) MRAP2 splice variants, MRAP2b (465 bp open reading frame) and MRAP2c (381 bp open reading frame). Human MRAP2s are different in C-termini. We investigated the effects of five isoforms of MRAPs, hMRAP1a, hMRAP1b, hMRAP2a, hMRAP2b, and hMRAP2c, on MC3R and MC4R pharmacology. At the hMC3R, hMRAP1a and hMRAP2c increased and hMRAP1b decreased the cell surface expression. hMRAP1a increased affinity to ACTH. Four MRAPs (hMRAP1a, hMRAP1b, hMRAP2a, and hMRAP2c) decreased the maximal responses in response to α-MSH and ACTH. For hMC4R, hMRAP1a, hMRAP2a, and hMRAP2c increased the cell surface expression of hMC4R. Human MRAP1b significantly increased affinity to ACTH while MRAP2a decreased affinity to ACTH. Human MRAP1a increased ACTH potency. MRAPs also affected hMC4R basal activities, with hMRAP1s increasing and hMRAP2s decreasing the basal activities. In summary, the newly identified splicing variants, hMRAP2b and hMRAP2c, could regulate MC3R and MC4R pharmacology. The two MRAP1s and three MRAP2s had differential effects on MC3R and MC4R trafficking, binding, and signaling. These findings led to a better understanding of the regulation of neural MCRs by MRAP1s and MRAP2s. Full article
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14 pages, 1286 KiB  
Review
Folic Acid, Folinic Acid, 5 Methyl TetraHydroFolate Supplementation for Mutations That Affect Epigenesis through the Folate and One-Carbon Cycles
by Yves Menezo, Kay Elder, Arthur Clement and Patrice Clement
Biomolecules 2022, 12(2), 197; https://doi.org/10.3390/biom12020197 - 24 Jan 2022
Cited by 46 | Viewed by 12365
Abstract
Methylation is an essential biochemical mechanism that is central to the transmission of life, and crucially responsible for regulating gametogenesis and continued embryo development. The methylation of DNA and histones drives cell division and regulation of gene expression through epigenesis and imprinting. Brain [...] Read more.
Methylation is an essential biochemical mechanism that is central to the transmission of life, and crucially responsible for regulating gametogenesis and continued embryo development. The methylation of DNA and histones drives cell division and regulation of gene expression through epigenesis and imprinting. Brain development and its maturation also depend on correct lipid methylation, and continued neuronal function depends on biogenic amines that require methylation for their synthesis. All methylation processes are carried out via a methyltransferase enzyme and its unique co-factor S-adenosylmethionine (SAM); the transfer of a methyl group to a target molecule results in the release of SAH (SA homocysteine), and then homocysteine (Hcy). Both of these molecules are toxic, inhibiting methylation in a variety of ways, and Hcy recycling to methionine is imperative; this is achieved via the one carbon cycle, supported by the folates cycle. Folate deficiency causes hyperhomocysteinaemia, with several associated diseases; during early pregnancy, deficiency interferes with closure of the neural tube at the fourth week of gestation, and nutraceutical supplementation has been routinely prescribed to prevent neural tube defects, mainly involving B vitamins, Zn and folates. The two metabolic pathways are subject to single nucleotide polymorphisms that alter their activity/capacity, often severely, impairing specific physiological functions including fertility, brain and cardiac function. The impact of three types of nutraceutical supplements, folic acid (FA), folinic acid (FLA) and 5 Methyl THF (MTHF), will be discussed here, with their positive effects alongside potentially hazardous secondary effects. The issue surrounding FA and its association with UMFA (unmetabolized folic acid) syndrome is now a matter of concern, as UMFA is currently found in the umbilical cord of the fetus, and even in infants’ blood. We will discuss its putative role in influencing the acquisition of epigenetic marks in the germline, acquired during embryogenesis, as well as the role of FA in the management of cancerous disease. Full article
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2021

Jump to: 2023, 2022

10 pages, 5782 KiB  
Review
Genome Editing among Bioethics and Regulatory Practices
by Mauro Mandrioli
Biomolecules 2022, 12(1), 13; https://doi.org/10.3390/biom12010013 - 22 Dec 2021
Cited by 3 | Viewed by 5186
Abstract
In the last decade, genome editing technologies became very effective and several clinical trials have been started in order to use them for treating some genetic diseases. Interestingly, despite more than 50 years of discussion about the frontiers of genetics in human health [...] Read more.
In the last decade, genome editing technologies became very effective and several clinical trials have been started in order to use them for treating some genetic diseases. Interestingly, despite more than 50 years of discussion about the frontiers of genetics in human health and evolution, the debate about the bioethics and the regulatory practices of genome editing is still far from satisfactory answers. This delay results from an excessive emphasis on the effectiveness of the genome editing technologies that is relevant for the regulatory practices, but not at a bioethical level. Indeed, other factors (such as accessibility and acceptability) could make these techniques not accepted at the bioethical level, even in the presence of their 100% effectiveness. Full article
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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: To be determined
Authors: Jungsu Kim; et al
Affiliation: Indiana University School of Medicine

Title: To be determined
Authors: Wolf-Dietrich Heyer; et al
Affiliation: University of California

Title: To be determined
Authors: Michael Ibba; et al
Affiliation: Ohio State University

Title: TMEM16x in genetic diseases
Authors: Paolo Scudieri; et al
Affiliation: U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy

Title: Functional characterization of a novel gene involved in a genetic neurodevelopmental disorder
Authors: Paolo Scudieri; et al.
Affiliation: U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy

Title: To be determined
Authors: Yves Menezo; et al.
Affiliation: Laboratoire Clement, Paris, France

Title: Advances in diagnosis and treatment of dystropinopathies
Authors: Corrado Angelini; et al
Affiliation: Department of Neurosciences, University of Padova, 35128 Padova, Italy

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