scholarly journals Shelterin components modulate nucleic acids condensation and phase separation

2021 ◽  
Author(s):  
Andrea Soranno ◽  
J. Jeremías Incicco ◽  
Paolo De Bona ◽  
Eric J. Tomko ◽  
Eric A. Galburt ◽  
...  
Keyword(s):  
Phase Separation ◽  
Single Molecule ◽  
Finite Size ◽  
Protein Composition ◽  
Nuclear Bodies ◽  
Scaffolding Protein ◽  
Single Chain ◽  
Dna Compaction ◽  
Pml Nuclear Bodies ◽  
The Relationship

AbstractTelomeres are nucleoprotein complexes that protect the ends of chromosomes and are essential for chromosome stability in Eukaryotes. In cells, individual telomeres form distinct globules of finite size that appear to be smaller than expected for bare DNA. Moreover, upon changes in their protein composition, telomeres can cluster to form telomere-induced-foci (TIFs) or co-localize with promyelocytic leukemia (PML) nuclear bodies. The physical basis for collapse of individual telomeres and coalescence of multiple ones remains unclear, as does the relationship between these two phenomena. By combining single-molecule measurements, optical microscopy, turbidity assays, and simulations, we show that the telomere scaffolding protein TRF2 can condense individual DNA chains and drives coalescence of multiple DNA molecules, leading to phase separation and the formation of liquid-like droplets. Addition of the TRF2 binding protein hRap1 modulates phase boundaries and tunes the specificity of solution demixing while simultaneously altering the degree of DNA compaction. Our results suggest that the condensation of single telomeres and formation of biomolecular condensates containing multiple telomeres are two different outcomes driven by the same set of molecular interactions. Moreover, binding partners, such as other telomere components, can alter those interactions to promote single-chain DNA compaction over multiple-chain phase separation.

scholarly journals HP1 proteins compact DNA into mechanically and positionally stable phase separated domains

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Madeline M Keenen ◽  
David Brown ◽  
Lucy D Brennan ◽  
Roman Renger ◽  
Harrison Khoo ◽  
...  
Keyword(s):  
Phase Separation ◽  
Single Molecule ◽  
Genome Organization ◽  
Stable Phase ◽  
Dna Molecules ◽  
Weakly Bound ◽  
Dna Compaction ◽  
Polymer Properties ◽  
Molecular Scale ◽  
Hp1 Proteins

In mammals, HP1-mediated heterochromatin forms positionally and mechanically stable genomic domains even though the component HP1 paralogs, HP1α, HP1β, and HP1γ, display rapid on-off dynamics. Here, we investigate whether phase-separation by HP1 proteins can explain these biological observations. Using bulk and single-molecule methods, we show that, within phase-separated HP1α-DNA condensates, HP1α acts as a dynamic liquid, while compacted DNA molecules are constrained in local territories. These condensates are resistant to large forces yet can be readily dissolved by HP1β. Finally, we find that differences in each HP1 paralog’s DNA compaction and phase-separation properties arise from their respective disordered regions. Our findings suggest a generalizable model for genome organization in which a pool of weakly bound proteins collectively capitalize on the polymer properties of DNA to produce self-organizing domains that are simultaneously resistant to large forces at the mesoscale and susceptible to competition at the molecular scale.

scholarly journals Computer modeling of phase separation at PML nuclear bodies

2019 ◽  
Vol 35 (3) ◽  
pp. 185-185
Author(s):  
R. Henze ◽  
M. Wenzel ◽  
P. Dittrich ◽  
P. Hemmerich
Keyword(s):  
Phase Separation ◽  
Computer Modeling ◽  
Nuclear Bodies ◽  
Pml Nuclear Bodies

scholarly journals HP1 proteins compact DNA into mechanically and positionally stable phase separated domains

2020 ◽  
Author(s):  
Madeline M. Keenen ◽  
David Brown ◽  
Lucy D. Brennan ◽  
Roman Renger ◽  
Harrison Khoo ◽  
...  
Keyword(s):  
Phase Separation ◽  
Single Molecule ◽  
Genome Organization ◽  
Stable Phase ◽  
Dna Molecules ◽  
Weakly Bound ◽  
Dna Compaction ◽  
Polymer Properties ◽  
Molecular Scale ◽  
Hp1 Proteins

In mammals HP1-mediated heterochromatin forms positionally and mechanically stable genomic domains even though the component HP1 paralogs, HP1α, HP1β, and HP1γ, display rapid on-off dynamics. Here we investigate whether phase-separation by HP1 proteins can explain these biological observations. Using bulk and single-molecule methods, we show that, within phase-separated HP1α-DNA condensates, HP1α acts as a dynamic liquid, while compacted DNA molecules are constrained in local territories. These condensates are resistant to large forces yet can be readily dissolved by HP1β. Finally, we find that differences in each HP1 paralog’s DNA compaction and phase-separation properties arise from their respective disordered regions. Our findings suggest a generalizable model for genome organization in which a pool of weakly bound proteins collectively capitalize on the polymer properties of DNA to produce self-organizing domains that are simultaneously resistant to large forces at the mesoscale and susceptible to competition at the molecular scale.

The localized electron: magnetic properties

2018 ◽  
Author(s):  
Jean-Pierre Launay ◽  
Michel Verdaguer
Keyword(s):  
Single Molecule ◽  
Model Systems ◽  
Ferromagnetic Coupling ◽  
Single Chain ◽  
Single Molecule Magnets ◽  
Magnetic Systems ◽  
Orbital Interactions ◽  
Prussian Blue Analogues ◽  
Mononuclear Complexes

After preliminaries about electron properties, and definitions in magnetism, one treats the magnetism of mononuclear complexes, in particular spin cross-over, showing the role of cooperativity and the sensitivity to external perturbations. Orbital interactions and exchange interaction are explained in binuclear model systems, using orbital overlap and orthogonality concepts to explain antiferromagnetic or ferromagnetic coupling. The phenomenologically useful Spin Hamiltonian is defined. The concepts are then applied to extended molecular magnetic systems, leading to molecular magnetic materials of various dimensionalities exhibiting bulk ferro- or ferrimagnetism. An illustration is provided by Prussian Blue analogues. Magnetic anisotropy is introduced. It is shown that in some cases, a slow relaxation of magnetization arises and gives rise to appealing single-ion magnets, single-molecule magnets or single-chain magnets, a route to store information at the molecular level.

scholarly journals Nuclear body phase separation drives telomere clustering in ALT cancer cells

2020 ◽  
Vol 31 (18) ◽  
pp. 2048-2056 ◽  
Author(s):  
Huaiying Zhang ◽  
Rongwei Zhao ◽  
Jason Tones ◽  
Michel Liu ◽  
Robert L. Dilley ◽  
...  
Keyword(s):  
Dna Repair ◽  
Phase Separation ◽  
Cancer Cells ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Telomere Elongation ◽  
Alternative Lengthening ◽  
Induce Phase Separation ◽  
Induce Phase

A chemical dimerization approach is developed to induce phase separation of APB nuclear bodies involved in telomere elongation in alternative lengthening of telomeres (ALT) cancer cells. It reveals that ALT telomere-associated promyelocytic leukemia nuclear body (APB) fusion leads to telomere clustering to provide templates for homology-directed telomere synthesis, an ability that is decoupled from APB function in enriching DNA repair factors.

scholarly journals Solvent Exposure and Ionic Condensation Drive Fuzzy Dimerization of Disordered Heterochromatin Protein Sequence

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 915
Author(s):  
Jazelli Mueterthies ◽  
Davit A. Potoyan
Keyword(s):  
Phase Separation ◽  
Low Complexity ◽  
Nuclear Bodies ◽  
Disordered Proteins ◽  
Solvent Exposure ◽  
Ion Release ◽  
Dimer Formation ◽  
Eukaryotic Organisms

Proteins with low complexity, disordered sequences are receiving increasing attention due to their central roles in the biogenesis and regulation of membraneless organelles. In eukaryotic organisms, a substantial fraction of disordered proteins reside in the nucleus, thereby facilitating the formation of nuclear bodies, nucleolus, and chromatin compartmentalization. The heterochromatin family of proteins (HP1) is an important player in driving the formation of gene silenced mesoscopic heterochromatin B compartments and pericentric regions. Recent experiments have shown that the HP1a sequence of Drosophila melanogaster can undergo liquid-liquid phase separation under both in vitro and in vivo conditions, induced by changes of the monovalent salt concentration. While the phase separation of HP1a is thought to be the mechanism underlying chromatin compartmentalization, the molecular level mechanistic picture of salt-driven phase separation of HP1a has remained poorly understood. The disordered hinge region of HP1a is seen as the driver of salt-induced condensation because of its charge enriched sequence and post-translational modifications. Here, we set out to decipher the mechanisms of salt-induced condensation of HP1a through a systematic study of salt-dependent conformations of single chains and fuzzy dimers of disordered HP1a hinge sequences. Using multiple independent all-atom simulations with and without enhanced sampling, we carry out detailed characterization of conformational ensembles of disordered HP1a chains under different ionic conditions using various polymeric and structural measures. We show that the mobile ion release, enhancement of local transient secondary structural elements, and side-chain exposure to solvent are robust trends that accompany fuzzy dimer formation. Furthermore, we find that salt-induced changes in the ensemble of conformations of HP1a disordered hinge sequence fine-tune the inter-chain vs. self-chain interactions in ways that favor fuzzy dimer formation under low salt conditions in the agreement with condensation trends seen in experiments.

CSF chitinase 3-like 1 is associated with iron rims in patients with a first demyelinating event

2021 ◽  
pp. 135245852110100
Author(s):  
Manuel Comabella ◽  
Margareta A Clarke ◽  
Sabine Schaedelin ◽  
Mar Tintoré ◽  
Deborah Pareto ◽  
...  
Keyword(s):  
Single Molecule ◽  
Multivariable Analysis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Lesion Volume ◽  
Univariable Analysis ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Multivariable Analyses ◽  
Prognostic Implications ◽  
The Relationship

Background: Chronic active lesions with iron rims have prognostic implications in patients with multiple sclerosis. Objective: To assess the relationship between iron rims and levels of chitinase 3-like 1 (CHI3L1), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in patients with a first demyelinating event. Methods: Iron rims were identified using 3T susceptibility-weighted imaging. Serum NfL and GFAP levels were measured by single-molecule array assays. CSF (cerebrospinal fluid) CHI3L1 levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: Sixty-one patients were included in the study. The presence of iron rims was associated with higher T2 lesion volume and higher number of gadolinium-enhancing lesions. In univariable analysis, having ⩾2 iron rims (vs 0) was associated with increased CSF CHI3L1 levels (β = 1.41; 95% confidence interval (CI) = 1.10–1.79; p < 0.01) and serum NfL levels (β = 2.30; 95% CI = 1.47–3.60; p < 0.01). In multivariable analysis, however, only CSF CHI3L1 levels remained significantly associated with the presence of iron rim lesions (β = 1.45; 95% CI = 1.11–1.90; p < 0.01). The presence of ⩾2 iron rims was not associated with increased serum GFAP levels in univariable or multivariable analyses. Conclusion: These findings support an important contribution of activated microglia/macrophages to the pathophysiology of chronic active lesions with iron rims in patients with a first demyelinating event.

scholarly journals Dynamic Nature of Cleavage Bodies and Their Spatial Relationship to DDX1 Bodies, Cajal Bodies, and Gems

2006 ◽  
Vol 17 (3) ◽  
pp. 1126-1140 ◽  
Author(s):  
Lei Li ◽  
Ken Roy ◽  
Sachin Katyal ◽  
Xuejun Sun ◽  
Stacey Bléoo ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Actin Polymerization ◽  
Spatial Relationship ◽  
S Phase ◽  
Nuclear Bodies ◽  
Cajal Bodies ◽  
Rna Transcription ◽  
Nuclear Structures ◽  
The Relationship ◽  
Striking Effect

DDX1 bodies, cleavage bodies, Cajal bodies (CBs), and gems are nuclear suborganelles that contain factors involved in RNA transcription and/or processing. Although all four nuclear bodies can exist as distinct entities, they often colocalize or overlap with each other. To better understand the relationship between these four nuclear bodies, we examined their spatial distribution as a function of the cell cycle. Here, we report that whereas DDX1 bodies, CBs and gems are present throughout interphase, CPSF-100-containing cleavage bodies are predominantly found during S and G2 phases, whereas CstF-64-containing cleavage bodies are primarily observed during S phase. All four nuclear bodies associate with each other during S phase, with cleavage bodies colocalizing with DDX1 bodies, and cleavage bodies/DDX1 bodies residing adjacent to gems and CBs. Although inhibitors of RNA transcription had no effect on DDX1 bodies or cleavage bodies, inhibitors of DNA replication resulted in loss of CstF-64-containing cleavage bodies. A striking effect on nuclear structures was observed with latrunculin B, an inhibitor of actin polymerization, resulting in the formation of needlelike nuclear spicules made up of CstF-64, CPSF-100, RNA, and RNA polymerase II. Our results suggest that cleavage body components are highly dynamic in nature.

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