scholarly journals Targeting Genome Integrity in Mycobacterium Tuberculosis: From Nucleotide Synthesis to DNA Replication and Repair

Molecules ◽  
2020 ◽  
Vol 25 (5) ◽  
pp. 1205 ◽  
Author(s):  
Riccardo Miggiano ◽  
Castrese Morrone ◽  
Franca Rossi ◽  
Menico Rizzi
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
Genome Stability ◽  
Current Knowledge ◽  
Genome Integrity ◽  
Dna Integrity ◽  
Dna Metabolism ◽  
Nucleotide Synthesis ◽  
Antitubercular Drugs ◽  
Molecular Events

Mycobacterium tuberculosis (MTB) is the causative agent of tuberculosis (TB), an ancient disease which still today causes 1.4 million deaths worldwide per year. Long-term, multi-agent anti-tubercular regimens can lead to the anticipated non-compliance of the patient and increased drug toxicity, which in turn can contribute to the emergence of drug-resistant MTB strains that are not susceptible to first- and second-line available drugs. Hence, there is an urgent need for innovative antitubercular drugs and vaccines. A number of biochemical processes are required to maintain the correct homeostasis of DNA metabolism in all organisms. Here we focused on reviewing our current knowledge and understanding of biochemical and structural aspects of relevance for drug discovery, for some such processes in MTB, and particularly DNA synthesis, synthesis of its nucleotide precursors, and processes that guarantee DNA integrity and genome stability. Overall, the area of drug discovery in DNA metabolism appears very much alive, rich of investigations and promising with respect to new antitubercular drug candidates. However, the complexity of molecular events that occur in DNA metabolic processes requires an accurate characterization of mechanistic details in order to avoid major flaws, and therefore the failure, of drug discovery approaches targeting genome integrity.

scholarly journals Mitochondrial DNA Integrity: Role in Health and Disease

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 100 ◽  
Author(s):  
Priyanka Sharma ◽  
Harini Sampath
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Genome Stability ◽  
Dna Lesions ◽  
Genome Integrity ◽  
Dna Integrity ◽  
Age Related ◽  
Genome Damage ◽  
Health And Disease ◽  
Mitochondrial Genome Stability

As the primary cellular location for respiration and energy production, mitochondria serve in a critical capacity to the cell. Yet, by virtue of this very function of respiration, mitochondria are subject to constant oxidative stress that can damage one of the unique features of this organelle, its distinct genome. Damage to mitochondrial DNA (mtDNA) and loss of mitochondrial genome integrity is increasingly understood to play a role in the development of both severe early-onset maladies and chronic age-related diseases. In this article, we review the processes by which mtDNA integrity is maintained, with an emphasis on the repair of oxidative DNA lesions, and the cellular consequences of diminished mitochondrial genome stability.

scholarly journals Inhibitors of pantothenate synthetase of Mycobacterium tuberculosis – a medicinal chemist perspective

RSC Advances ◽  
2020 ◽  
Vol 10 (61) ◽  
pp. 37098-37115
Author(s):  
Amaroju Suresh ◽  
Singireddi Srinivasarao ◽  
Yogesh Mahadu Khetmalis ◽  
Shashidhar Nizalapur ◽  
Murugesan Sankaranarayanan ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
Antitubercular Drugs ◽  
New Drug ◽  
Current Review ◽  
Pantothenate Synthetase

Tuberculosis, leads to numerous deaths worldwide. New drug discovery strategies are need of the hour. In the current review, we focused on the discovery of new antitubercular drugs targeting pantothenate synthetase.

Aim for the Readers! Bromodomains As New Targets Against Chagas’ Disease

2019 ◽  
Vol 26 (36) ◽  
pp. 6544-6563
Author(s):  
Victoria Lucia Alonso ◽  
Luis Emilio Tavernelli ◽  
Alejandro Pezza ◽  
Pamela Cribb ◽  
Carla Ritagliati ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Chagas Disease ◽  
Causative Agent ◽  
Current Knowledge ◽  
Sequence Similarity ◽  
Lysine Acetylation ◽  
Specific Manner ◽  
Lysine Residues ◽  
Antiparasitic Drugs

Bromodomains recognize and bind acetyl-lysine residues present in histone and non-histone proteins in a specific manner. In the last decade they have raised as attractive targets for drug discovery because the miss-regulation of human bromodomains was discovered to be involved in the development of a large spectrum of diseases. However, targeting eukaryotic pathogens bromodomains continues to be almost unexplored. We and others have reported the essentiality of diverse bromodomain- containing proteins in protozoa, offering a new opportunity for the development of antiparasitic drugs, especially for Trypansoma cruzi, the causative agent of Chagas’ disease. Mammalian bromodomains were classified in eight groups based on sequence similarity but parasitic bromodomains are very divergent proteins and are hard to assign them to any of these groups, suggesting that selective inhibitors can be obtained. In this review, we describe the importance of lysine acetylation and bromodomains in T. cruzi as well as the current knowledge on mammalian bromodomains. Also, we summarize the myriad of small-molecules under study to treat different pathologies and which of them have been tested in trypanosomatids and other protozoa. All the information available led us to propose that T. cruzi bromodomains should be considered as important potential targets and the search for smallmolecules to inhibit them should be empowered.

scholarly journals A Comprehensive Review on Solitary Fibrous Tumor: New Insights for New Horizons

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2913
Author(s):  
Javier Martin-Broto ◽  
Jose L. Mondaza-Hernandez ◽  
David S. Moura ◽  
Nadia Hindi
Keyword(s):  
Solitary Fibrous Tumor ◽  
Fusion Gene ◽  
Current Knowledge ◽  
Fusion Transcript ◽  
Chemotherapeutic Agents ◽  
Comprehensive Review ◽  
Molecular Events ◽  
In Series ◽  
Prospective Phase ◽  
Fibrous Tumor

Solitary fibrous tumor (SFT) is a rare mesenchymal, ubiquitous tumor, with an incidence of 1 new case/million people/year. In the 2020 WHO classification, risk stratification models were recommended as a better tool to determine prognosis in SFT, to the detriment of “typical” or “malignant” classic terms. The risk for metastasis is up to 35–45%, or even greater, in series with a longer follow-up. Over the last few decades, advances in immunohistochemistry and molecular diagnostics identified STAT6 nuclear protein expression and the NAB2–STAT6 fusion gene as more precise tools for SFT diagnosis. Recent evidence taken from retrospective series and from two prospective phase II clinical trials showed that antiangiogenics are active and their sequential use from first line should be considered, except for dedifferentiated SFT for which chemotherapy is the best option. Since the fusion transcript driver’s first description in 2013, new insights have been brought on key molecular events in SFT. This comprehensive review mainly focuses on the superior efficacy of antiangiogenics over chemotherapeutic agents in SFT, provides the current knowledge of key molecules that could co-drive the SFT behavior, and suggests new target candidates that deserve to be explored in preclinical and clinical research in SFT.

scholarly journals Emerging Roles of RAD52 in Genome Maintenance

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1038 ◽  
Author(s):  
Manisha Jalan ◽  
Kyrie S. Olsen ◽  
Simon N. Powell
Keyword(s):  
Genome Stability ◽  
Genome Integrity ◽  
Repair Pathway ◽  
Genome Maintenance ◽  
Knock Out ◽  
Repair Protein ◽  
Attractive Therapeutic Target ◽  
Dna Repair Protein ◽  
Synthetically Lethal ◽  
Knock Out Mice

The maintenance of genome integrity is critical for cell survival. Homologous recombination (HR) is considered the major error-free repair pathway in combatting endogenously generated double-stranded lesions in DNA. Nevertheless, a number of alternative repair pathways have been described as protectors of genome stability, especially in HR-deficient cells. One of the factors that appears to have a role in many of these pathways is human RAD52, a DNA repair protein that was previously considered to be dispensable due to a lack of an observable phenotype in knock-out mice. In later studies, RAD52 deficiency has been shown to be synthetically lethal with defects in BRCA genes, making RAD52 an attractive therapeutic target, particularly in the context of BRCA-deficient tumors.

scholarly journals The β-oxidation pathway is downregulated during diapause termination in Calanus copepods

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Elise Skottene ◽  
Ann M. Tarrant ◽  
Anders J. Olsen ◽  
Dag Altin ◽  
Mari-Ann Østensen ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Juvenile Fish ◽  
Sampling Site ◽  
Geographical Location ◽  
Keystone Species ◽  
Calanoid Copepods ◽  
Diapause Termination ◽  
Molecular Events ◽  
High Lipid ◽  
Field Samples

Abstract Calanus copepods are keystone species in marine ecosystems, mainly due to their high lipid content, which is a nutritious food source for e.g. juvenile fish. Accumulated lipids are catabolized to meet energy requirements during dormancy (diapause), which occurs during the last copepodite stage (C5). The current knowledge of lipid degradation pathways during diapause termination is limited. We characterized changes in lipid fullness and generated transcriptional profiles in C5s during termination of diapause and progression towards adulthood. Lipid fullness of C5s declined linearly during developmental progression, but more β-oxidation genes were upregulated in early C5s compared to late C5s and adults. We identified four possible master regulators of energy metabolism, which all were generally upregulated in early C5s, compared to late C5s and adults. We discovered that one of two enzymes in the carnitine shuttle is absent from the calanoid copepod lineage. Based on the geographical location of the sampling site, the field-samples were initially presumed to consist of C. finmarchicus. However, the identification of C. glacialis in some samples underlines the need for performing molecular analyses to reliably identify Calanus species. Our findings contributes to a better understanding of molecular events occurring during diapause and diapause termination in calanoid copepods.

scholarly journals The Mycobacterium tuberculosis PE_PGRS Protein Family Acts as an Immunological Decoy to Subvert Host Immune Response

2022 ◽  
Vol 23 (1) ◽  
pp. 525
Author(s):  
Tarina Sharma ◽  
Anwar Alam ◽  
Aquib Ehtram ◽  
Anshu Rani ◽  
Sonam Grover ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Current Knowledge ◽  
Immune Effector ◽  
Host Immune Responses ◽  
Intrinsically Disordered ◽  
Multiple Strategies ◽  
Latent Stage ◽  
Immune Mediated ◽  
Critical Edge

Mycobacterium tuberculosis (M.tb) is a successful pathogen that can reside within the alveolar macrophages of the host and can survive in a latent stage. The pathogen has evolved and developed multiple strategies to resist the host immune responses. M.tb escapes from host macrophage through evasion or subversion of immune effector functions. M.tb genome codes for PE/PPE/PE_PGRS proteins, which are intrinsically disordered, redundant and antigenic in nature. These proteins perform multiple functions that intensify the virulence competence of M.tb majorly by modulating immune responses, thereby affecting immune mediated clearance of the pathogen. The highly repetitive, redundant and antigenic nature of PE/PPE/PE_PGRS proteins provide a critical edge over other M.tb proteins in terms of imparting a higher level of virulence and also as a decoy molecule that masks the effect of effector molecules, thereby modulating immuno-surveillance. An understanding of how these proteins subvert the host immunological machinery may add to the current knowledge about M.tb virulence and pathogenesis. This can help in redirecting our strategies for tackling M.tb infections.

scholarly journals Genome Maintenance Mechanisms at the Chromatin Level

2021 ◽  
Vol 22 (19) ◽  
pp. 10384
Author(s):  
Hirotomo Takatsuka ◽  
Atsushi Shibata ◽  
Masaaki Umeda
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genome Stability ◽  
Genotoxic Stress ◽  
Genome Integrity ◽  
Easy Access ◽  
Order Structure ◽  
Chromatin Modifications ◽  
Level Control ◽  
Regulatory Systems

Genome integrity is constantly threatened by internal and external stressors, in both animals and plants. As plants are sessile, a variety of environment stressors can damage their DNA. In the nucleus, DNA twines around histone proteins to form the higher-order structure “chromatin”. Unraveling how chromatin transforms on sensing genotoxic stress is, thus, key to understanding plant strategies to cope with fluctuating environments. In recent years, accumulating evidence in plant research has suggested that chromatin plays a crucial role in protecting DNA from genotoxic stress in three ways: (1) changes in chromatin modifications around damaged sites enhance DNA repair by providing a scaffold and/or easy access to DNA repair machinery; (2) DNA damage triggers genome-wide alterations in chromatin modifications, globally modulating gene expression required for DNA damage response, such as stem cell death, cell-cycle arrest, and an early onset of endoreplication; and (3) condensed chromatin functions as a physical barrier against genotoxic stressors to protect DNA. In this review, we highlight the chromatin-level control of genome stability and compare the regulatory systems in plants and animals to find out unique mechanisms maintaining genome integrity under genotoxic stress.

scholarly journals Reduced Shmt2 expression impairs mitochondrial folate accumulation and respiration, and leads to uracil accumulation in mouse mitochondrial DNA

2021 ◽  
Author(s):  
Joanna L Fiddler ◽  
Yuwen Xiu ◽  
Jamie E Blum ◽  
Simon G Lamarre ◽  
Whitney N Phinney ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Folic Acid ◽  
Mitochondrial Function ◽  
Genome Stability ◽  
Control Diet ◽  
Folate Deficiency ◽  
Dna Integrity ◽  
Dietary Folate ◽  
Mouse Tissues ◽  
Defined Culture

Background. Adequate cellular thymidylate (dTMP) pools are essential for preservation of nuclear and mitochondrial genome stability. Previous studies have indicated that disruption in dTMP synthesis in the nucleus leads to increased uracil misincorporation into DNA affecting genome stability. To date, the effects of impaired mitochondrial dTMP synthesis in non-transformed tissues have been understudied. Objective. This study aimed to determine the effects of decreased serine hydroxymethyltransferase 2 (Shmt2) expression and dietary folate deficiency on mitochondrial DNA integrity and mitochondrial function in mouse tissues. Methods. Liver mitochondrial DNA (mtDNA) content, and uracil content in liver mtDNA was measured in Shmt2+/- and Shmt2+/+ mice weaned onto either a folate-sufficient control diet (2 mg/kg folic acid, C) or a modified diet lacking folic acid (0 mg/kg folic acid, FD) for 7 wks. Shmt2+/- and Shmt2+/+ mouse embryonic fibroblasts (MEF cells) were cultured in defined culture medium containing either 0 or 25 nM folate to assess proliferative capacity and mitochondrial function. Results. Shmt2+/- mice exhibited 48-67% reduction in SHMT2 protein levels in tissues. Interestingly, Shmt2+/- mice consuming the folate-sufficient C diet exhibited a 25% reduction in total folate in liver mitochondria. There was also a >20-fold increase in uracil in liver mtDNA in Shmt2+/- mice consuming the C diet, and dietary folate deficiency also increased uracil content in mouse liver mtDNA from both Shmt2+/+ and Shmt2+/- mice. Furthermore, decreased Shmt2 expression in MEF cells reduced cell proliferation, mitochondrial membrane potential, and oxygen consumption rate. Conclusions. This study demonstrates that Shmt2 heterozygosity and dietary folate deficiency impair mitochondrial dTMP synthesis, as evidenced by the increased uracil in mtDNA. In addition, Shmt2 heterozygosity impairs mitochondrial function in MEF cells. These findings suggest that elevated uracil in mtDNA may impair mitochondrial function.

scholarly journals Heterochromatin: Guardian of the Genome

2018 ◽  
Vol 34 (1) ◽  
pp. 265-288 ◽  
Author(s):  
Aniek Janssen ◽  
Serafin U. Colmenares ◽  
Gary H. Karpen
Keyword(s):  
Chromosome Segregation ◽  
Genome Stability ◽  
Constitutive Heterochromatin ◽  
Repetitive Sequences ◽  
Genome Integrity ◽  
Chromatin Domain ◽  
Cellular Processes ◽  
Eukaryotic Nucleus ◽  
And Function ◽  
Heterochromatin Structure

Constitutive heterochromatin is a major component of the eukaryotic nucleus and is essential for the maintenance of genome stability. Highly concentrated at pericentromeric and telomeric domains, heterochromatin is riddled with repetitive sequences and has evolved specific ways to compartmentalize, silence, and repair repeats. The delicate balance between heterochromatin epigenetic maintenance and cellular processes such as mitosis and DNA repair and replication reveals a highly dynamic and plastic chromatin domain that can be perturbed by multiple mechanisms, with far-reaching consequences for genome integrity. Indeed, heterochromatin dysfunction provokes genetic turmoil by inducing aberrant repeat repair, chromosome segregation errors, transposon activation, and replication stress and is strongly implicated in aging and tumorigenesis. Here, we summarize the general principles of heterochromatin structure and function, discuss the importance of its maintenance for genome integrity, and propose that more comprehensive analyses of heterochromatin roles in tumorigenesis will be integral to future innovations in cancer treatment.

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