scholarly journals How Not To Be in the Wrong Place at the Wrong Time: An Education Primer for Use with “Deposition of Centromeric Histone H3 Variant CENP-A/Cse4 into Chromatin Is Facilitated by Its C-Terminal Sumoylation”

Genetics ◽  
2020 ◽  
Vol 216 (2) ◽  
pp. 333-342
Author(s):  
Yee Mon Thu
Keyword(s):  
Molecular Mechanisms ◽  
Genetic Diseases ◽  
Histone H3 ◽  
Model Organism ◽  
Post Translational Modification ◽  
Genetic Changes ◽  
Equal Distribution ◽  
Link Type ◽  
Histone H3 Variant ◽  
Big Picture

Recent work by Kentaro Ohkuni and colleagues exemplifies how a series of molecular mechanisms contribute to a cellular outcome—equal distribution of chromosomes. Failure to maintain structural and numerical integrity of chromosomes is one contributing factor in genetic diseases such as cancer. Specifically, the authors investigated molecular events surrounding centromeric histone H3 variant Cse4 deposition—a process important for chromosome segregation, using Saccharomyces cerevisiae as a model organism. This study illustrates an example of a post-translational modification—sumoylation—regulating a cellular process and the concept of genetic interactions (e.g., synthetic dosage lethality). Furthermore, the study highlights the importance of using diverse experimental approaches in answering a few key research questions. The authors used molecular biology techniques (e.g., qPCR), biochemical experiments (e.g., Ni-NTA/8His protein purification), as well as genetic approaches to understand the regulation of Cse4. At a big-picture level, the study reveals how genetic changes can lead to subsequent molecular and cellular changes.

scholarly journals Deposition of Centromeric Histone H3 Variant CENP-A/Cse4 into Chromatin Is Facilitated by Its C-Terminal Sumoylation

Genetics ◽  
2020 ◽  
Vol 214 (4) ◽  
pp. 839-854 ◽  
Author(s):  
Kentaro Ohkuni ◽  
Evelyn Suva ◽  
Wei-Chun Au ◽  
Robert L. Walker ◽  
Reuben Levy-Myers ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Histone Chaperones ◽  
Wild Type ◽  
Link Type ◽  
C Terminus ◽  
Genome Wide ◽  
Evolutionarily Conserved ◽  
Histone H3 Variant ◽  
Assembly Factor ◽  
Active Investigation

Centromeric localization of CENP-A (Cse4 in Saccharomyces cerevisiae, CID in flies, CENP-A in humans) is essential for faithful chromosome segregation. Mislocalization of overexpressed CENP-A contributes to aneuploidy in yeast, flies, and humans, and is proposed to promote tumorigenesis in human cancers. Hence, defining molecular mechanisms that promote or prevent mislocalization of CENP-A is an area of active investigation. In budding yeast, evolutionarily conserved histone chaperones Scm3 and chromatin assembly factor-1 (CAF-1) promote localization of Cse4 to centromeric and noncentromeric regions, respectively. Ubiquitin ligases, such as Psh1 and Slx5, and histone chaperones (HIR complex) regulate proteolysis of overexpressed Cse4 and prevent its mislocalization to noncentromeric regions. In this study, we have identified sumoylation sites lysine (K) 215/216 in the C terminus of Cse4, and shown that sumoylation of Cse4 K215/216 facilitates its genome-wide deposition into chromatin when overexpressed. Our results showed reduced levels of sumoylation of mutant Cse4 K215/216R/A [K changed to arginine (R) or alanine (A)] and reduced interaction of mutant Cse4 K215/216R/A with Scm3 and CAF-1 when compared to wild-type Cse4. Consistent with these results, levels of Cse4 K215/216R/A in the chromatin fraction and localization to centromeric and noncentromeric regions were reduced. Furthermore, in contrast to GAL-CSE4, which exhibits Synthetic Dosage Lethality (SDL) in psh1∆, slx5∆, and hir2∆ strains, GAL-cse4 K215/216R does not exhibit SDL in these strains. Taken together, our results show that deposition of Cse4 into chromatin is facilitated by its C-terminal sumoylation.

scholarly journals The incorporation loci of H3.3K36M determine its preferential prevalence in chondroblastomas

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Yanjun Zhang ◽  
Dong Fang
Keyword(s):  
Gene Expression ◽  
Colony Formation ◽  
Molecular Mechanisms ◽  
Histone H3 ◽  
Mutant Protein ◽  
H3k36 Methylation ◽  
Mutant Proteins ◽  
Histone H3 Variant ◽  
Mutant Cells ◽  
Shed Light

AbstractThe histone H3.3K36M mutation, identified in over 90% of chondroblastoma cases, reprograms the H3K36 methylation landscape and gene expression to promote tumorigenesis. However, it’s still unclear how the H3K36M mutation preferentially occurs in the histone H3 variant H3.3 in chondroblastomas. Here, we report that H3.3K36M-, but not H3.1K36M-, mutant cells showed increased colony formation ability and differentiation defects. H3K36 methylations and enhancers were reprogrammed to different status in H3.3K36M- and H3.1K36M-mutant cells. The reprogramming of H3K36 methylation and enhancers was depended on the specific loci at which H3.3K36M and H3.1K36M were incorporated. Moreover, targeting H3K36M-mutant proteins to the chromatin inhibited the H3K36 methylation locally. Taken together, these results highlight the roles of the chromatic localization of H3.3K36M-mutant protein in the reprogramming of the epigenome and the subsequent induction of tumorigenesis, and shed light on the molecular mechanisms by which the H3K36M mutation mainly occurs in histone H3.3 in chondroblastomas.

scholarly journals Xenopus: An Undervalued Model Organism to Study and Model Human Genetic Disease

2018 ◽  
Vol 205 (5-6) ◽  
pp. 303-313 ◽  
Author(s):  
Martin Blum ◽  
Tim Ott
Keyword(s):  
High Speed ◽  
Molecular Mechanisms ◽  
Genetic Diseases ◽  
Model Organism ◽  
Model Organisms ◽  
Human Genetic Disease ◽  
The Past ◽  
Large Numbers ◽  
Pros And Cons ◽  
Cost Efficient

The function of normal and defective candidate genes for human genetic diseases, which are rapidly being identified in large numbers by human geneticists and the biomedical community at large, will be best studied in relevant and predictive model organisms that allow high-speed verification, analysis of underlying developmental, cellular and molecular mechanisms, and establishment of disease models to test therapeutic options. We describe and discuss the pros and cons of the frog Xenopus, which has been extensively used to uncover developmental mechanisms in the past, but which is being underutilized as a biomedical model. We argue that Xenopus complements the more commonly used mouse and zebrafish as a time- and cost-efficient animal model to study human disease alleles and mechanisms.

scholarly journals Centromeric chromatin gets loaded

2007 ◽  
Vol 176 (6) ◽  
pp. 735-736 ◽  
Author(s):  
Christopher W. Carroll ◽  
Aaron F. Straight
Keyword(s):  
Chromosome Segregation ◽  
Molecular Mechanisms ◽  
Protein A ◽  
Histone H3 ◽  
Chromatin Assembly ◽  
Centromeric Chromatin ◽  
Kinetochore Assembly ◽  
Centromere Protein A ◽  
Specific Loading ◽  
Histone H3 Variant

Centromeric nucleosomes contain a histone H3 variant called centromere protein A (CENP-A) that is required for kinetochore assembly and chromosome segregation. Two new studies, Jansen et al. (see p. 795 of this issue) and Maddox et al. (see p. 757 of this issue), address when CENP-A is deposited at centromeres during the cell division cycle and identify an evolutionally conserved protein required for CENP-A deposition. Together, these studies advance our understanding of centromeric chromatin assembly and provide a framework for investigating the molecular mechanisms that underlie the centromere-specific loading of CENP-A.

WORKSHOP ABSTRACTS

2006 ◽  
Vol 10 (13) ◽  
pp. 88-155
Keyword(s):  
Cancer Progression ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Academic Career ◽  
Human Cancer ◽  
Genetic Diseases ◽  
Genomic Medicine ◽  
Genetic Changes ◽  
Antiviral Therapies

SCBA Special WORKSHOP #1 NIH WORKSHOP NIH — Goes Electronic: How to Get Grants In the E-age? SCBA Special WORKSHOP #2 ACGA WORKSHOP — Genetic Diseases and Genomic Medicine. SCBA Special WORKSHOP #3 Genetic Changes and Mechanisms Contributing to Human Cancer. SCBA Special WORKSHOP #4 Upward Mobility in the Industrial and Academic Career. SCBA WORKSHOP #1: RNA Interference. SCBA WORKSHOP #2: Vaccine and Antiviral Therapies. SCBA WORKSHOP #3: Regulation and Modification of p53. SCBA WORKSHOP #4: Opioid Receptors: Molecules, Cells and the Whole Animal. SCBA WORKSHOP #5: Nuclear Receptor. SCBA WORKSHOP #6: Immune Responses and Signaling. SCBA WORKSHOP #7: Frontiers in Gene Therapy. SCBA WORKSHOP #8: Pathogenesis and Treatments of Neurophsychiatric and Neurodegenerative Diseases: New Understandings and New Possibilities. SCBA WORKSHOP #9: Nanotechnologies and Microfluidics for Biotech Application. SCBA WORKSHOP #10: Basic Mechanisms of Ubiquitination, NEDDDylation ISG-15 Modification. SCBA WORKSHOP #11: Neuronal Signaling and Synaptic Plasticity. SCBA WORKSHOP #12: Signal Transduction 1. SCBA WORKSHOP #13: Chemical Genetics. SCBA WORKSHOP #14: Plant Science and Epigenics Biology. SCBA WORKSHOP #15: Cytokines and Inflammation. SCBA WORKSHOP #16: Novel Post-Translation Modifications. SCBA WORKSHOP #17: Translational Medicine. SCBA WORKSHOP #18: Acetylationa in Ubiquitinatio in Chromatin-Templated Processes. SCBA WORKSHOP #19: Pathogenesis of Viral Infections. SCBA WORKSHOP #20: Stem Cell Biology and Regenerative Medicine. SCBA WORKSHOP #21: Biotech Panel: The making of a Successful Biotech Company. SCBA WORKSHOP #22: Molecular Mechanisms of Cancer Progression and Therapeutic Resistance. SCBA WORKSHOP #23: Regulatory Geneomics and Epigenomics. SCBA WORKSHOP #24: RNA Biology. SCBA WORKSHOP #25: Bioprocessing. SCBA WORKSHOP #26: Recent Development of Targeted Therapy. SCBA WORKSHOP #27: DNA Damage Response in Eukaryotes. SCBA WORKSHOP #28: The Biology and Promise of Neural Stem Cells. SCBA WORKSHOP #29: IP and Business Licensing. SCBA WORKSHOP #30: Basic Mechanisms of Sumoylation. SCBA WORKSHOP #31: Immune Regulation and Therapy. SCBA WORKSHOP #32: Proteomics and Applications.

The Mechanisms Behind the Biological Activity of Flavonoids

2019 ◽  
Vol 26 (39) ◽  
pp. 6976-6990 ◽  
Author(s):  
Ana María González-Paramás ◽  
Begoña Ayuda-Durán ◽  
Sofía Martínez ◽  
Susana González-Manzano ◽  
Celestino Santos-Buelga
Keyword(s):  
Gene Expression ◽  
Biological Activity ◽  
Phenolic Compounds ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Radical Scavenging ◽  
Model Organism ◽  
Stress Theory ◽  
Radical Scavenging Properties

: Flavonoids are phenolic compounds widely distributed in the human diet. Their intake has been associated with a decreased risk of different diseases such as cancer, immune dysfunction or coronary heart disease. However, the knowledge about the mechanisms behind their in vivo activity is limited and still under discussion. For years, their bioactivity was associated with the direct antioxidant and radical scavenging properties of phenolic compounds, but nowadays this assumption is unlikely to explain their putative health effects, or at least to be the only explanation for them. New hypotheses about possible mechanisms have been postulated, including the influence of the interaction of polyphenols and gut microbiota and also the possibility that flavonoids or their metabolites could modify gene expression or act as potential modulators of intracellular signaling cascades. This paper reviews all these topics, from the classical view as antioxidants in the context of the Oxidative Stress theory to the most recent tendencies related with the modulation of redox signaling pathways, modification of gene expression or interactions with the intestinal microbiota. The use of C. elegans as a model organism for the study of the molecular mechanisms involved in biological activity of flavonoids is also discussed.

Molecular Mechanisms of Complement System Proteins and Matrix Metalloproteinases in the Pathogenesis of Age-Related Macular Degeneration

2019 ◽  
Vol 19 (10) ◽  
pp. 705-718 ◽  
Author(s):  
Naima Mansoor ◽  
Fazli Wahid ◽  
Maleeha Azam ◽  
Khadim Shah ◽  
Anneke I. den Hollander ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Macular Degeneration ◽  
Complement System ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Age Related Macular Degeneration ◽  
Genetic Changes ◽  
Complement System Proteins ◽  
Age Related ◽  
Common Genetic Variants

: Age-related macular degeneration (AMD) is an eye disorder affecting predominantly the older people above the age of 50 years in which the macular region of the retina deteriorates, resulting in the loss of central vision. The key factors associated with the pathogenesis of AMD are age, smoking, dietary, and genetic risk factors. There are few associated and plausible genes involved in AMD pathogenesis. Common genetic variants (with a minor allele frequency of >5% in the population) near the complement genes explain 40–60% of the heritability of AMD. The complement system is a group of proteins that work together to destroy foreign invaders, trigger inflammation, and remove debris from cells and tissues. Genetic changes in and around several complement system genes, including the CFH, contribute to the formation of drusen and progression of AMD. Similarly, Matrix metalloproteinases (MMPs) that are normally involved in tissue remodeling also play a critical role in the pathogenesis of AMD. MMPs are involved in the degradation of cell debris and lipid deposits beneath retina but with age their functions get affected and result in the drusen formation, succeeding to macular degeneration. In this review, AMD pathology, existing knowledge about the normal and pathological role of complement system proteins and MMPs in the eye is reviewed. The scattered data of complement system proteins, MMPs, drusenogenesis, and lipofusogenesis have been gathered and discussed in detail. This might add new dimensions to the understanding of molecular mechanisms of AMD pathophysiology and might help in finding new therapeutic options for AMD.

scholarly journals Xyloglucan processing machinery in Xanthomonas pathogens and its role in the transcriptional activation of virulence factors

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Plinio S. Vieira ◽  
Isabela M. Bonfim ◽  
Evandro A. Araujo ◽  
Ricardo R. Melo ◽  
Augusto R. Lima ◽  
...  
Keyword(s):  
Virulence Factors ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Model Organism ◽  
Citrus Canker ◽  
Effector Proteins ◽  
Glycoside Hydrolases ◽  
Host Cells ◽  
System A ◽  
Enzymatic Machinery

AbstractXyloglucans are highly substituted and recalcitrant polysaccharides found in the primary cell walls of vascular plants, acting as a barrier against pathogens. Here, we reveal that the diverse and economically relevant Xanthomonas bacteria are endowed with a xyloglucan depolymerization machinery that is linked to pathogenesis. Using the citrus canker pathogen as a model organism, we show that this system encompasses distinctive glycoside hydrolases, a modular xyloglucan acetylesterase and specific membrane transporters, demonstrating that plant-associated bacteria employ distinct molecular strategies from commensal gut bacteria to cope with xyloglucans. Notably, the sugars released by this system elicit the expression of several key virulence factors, including the type III secretion system, a membrane-embedded apparatus to deliver effector proteins into the host cells. Together, these findings shed light on the molecular mechanisms underpinning the intricate enzymatic machinery of Xanthomonas to depolymerize xyloglucans and uncover a role for this system in signaling pathways driving pathogenesis.

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