Let's get physical – mechanisms of crossover interference

ABSTRACT The formation of crossovers between homologous chromosomes is key to sexual reproduction. In most species, crossovers are spaced further apart than would be expected if they formed independently, a phenomenon termed crossover interference. Despite more than a century of study, the molecular mechanisms implementing crossover interference remain a subject of active debate. Recent findings of how signaling proteins control the formation of crossovers and about the interchromosomal interface in which crossovers form offer new insights into this process. In this Review, we present a cell biological and biophysical perspective on crossover interference, summarizing the evidence that links interference to the spatial, dynamic, mechanical and molecular properties of meiotic chromosomes. We synthesize this physical understanding in the context of prevailing mechanistic models that aim to explain how crossover interference is implemented.

Download Full-text

Physical basis for long-distance communication along meiotic chromosomes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1801920115 ◽

2018 ◽

Vol 115 (40) ◽

pp. E9333-E9342 ◽

Cited By ~ 9

Author(s):

Kyle R. Fowler ◽

Randy W. Hyppa ◽

Gareth A. Cromie ◽

Gerald R. Smith

Keyword(s):

Fission Yeast ◽

Strand Break ◽

Physical Basis ◽

Long Distance ◽

Homologous Chromosomes ◽

Crossover Interference ◽

Meiotic Chromosomes ◽

Dna Double Strand Break ◽

Distance Communication ◽

Multiple Levels

Viable gamete formation requires segregation of homologous chromosomes connected, in most species, by cross-overs. DNA double-strand break (DSB) formation and the resulting cross-overs are regulated at multiple levels to prevent overabundance along chromosomes. Meiotic cells coordinate these events between distant sites, but the physical basis of long-distance chromosomal communication has been unknown. We show that DSB hotspots up to ∼200 kb (∼35 cM) apart form clusters via hotspot-binding proteins Rec25 and Rec27 in fission yeast. Clustering coincides with hotspot competition and interference over similar distances. Without Tel1 (an ATM tumor-suppressor homolog), DSB and crossover interference become negative, reflecting coordinated action along a chromosome. These results indicate that DSB hotspots within a limited chromosomal region and bound by their protein determinants form a clustered structure that, via Tel1, allows only one DSB per region. Such a “roulette” process within clusters explains the observed pattern of crossover interference in fission yeast. Key structural and regulatory components of clusters are phylogenetically conserved, suggesting conservation of this vital regulation. Based on these observations, we propose a model and discuss variations in which clustering and competition between DSB sites leads to DSB interference and in turn produces crossover interference.

Download Full-text

The Budding Yeast Msh4 Protein Functions in Chromosome Synapsis and the Regulation of Crossover Distribution

Genetics ◽

10.1093/genetics/158.3.1013 ◽

2001 ◽

Vol 158 (3) ◽

pp. 1013-1025 ◽

Cited By ~ 7

Author(s):

Janet E Novak ◽

Petra B Ross-Macdonald ◽

G Shirleen Roeder

Keyword(s):

Mismatch Repair ◽

Budding Yeast ◽

Null Mutation ◽

Crossing Over ◽

Wild Type ◽

Crossover Interference ◽

Meiotic Chromosomes ◽

Chromosome Synapsis ◽

Protein Functions ◽

Or Gene

AbstractThe budding yeast MSH4 gene encodes a MutS homolog produced specifically in meiotic cells. Msh4 is not required for meiotic mismatch repair or gene conversion, but it is required for wild-type levels of crossing over. Here, we show that a msh4 null mutation substantially decreases crossover interference. With respect to the defect in interference and the level of crossing over, msh4 is similar to the zip1 mutant, which lacks a structural component of the synaptonemal complex (SC). Furthermore, epistasis tests indicate that msh4 and zip1 affect the same subset of meiotic crossovers. In the msh4 mutant, SC formation is delayed compared to wild type, and full synapsis is achieved in only about half of all nuclei. The simultaneous defects in synapsis and interference observed in msh4 (and also zip1 and ndj1/tam1) suggest a role for the SC in mediating interference. The Msh4 protein localizes to discrete foci on meiotic chromosomes and colocalizes with Zip2, a protein involved in the initiation of chromosome synapsis. Both Zip2 and Zip1 are required for the normal localization of Msh4 to chromosomes, raising the possibility that the zip1 and zip2 defects in crossing over are indirect, resulting from the failure to localize Msh4 properly.

Download Full-text

Clinical and Biological Characteristics of Medullary and Extramedullary Plasma Cell Dyscrasias

Biology ◽

10.3390/biology10070629 ◽

2021 ◽

Vol 10 (7) ◽

pp. 629

Author(s):

Snjezana Janjetovic ◽

Philipp Lohneis ◽

Axel Nogai ◽

Derya Balci ◽

Leo Rasche ◽

...

Keyword(s):

Plasma Cell ◽

Molecular Mechanisms ◽

Biological Characteristics ◽

Surface Glycoprotein ◽

Cell Surface Glycoprotein ◽

Similar Frequency ◽

Cytogenetic Aberrations ◽

A Cell ◽

Plasma Cell Dyscrasias ◽

Extramedullary Plasmocytoma

Background: Extramedullary plasma cell (PC) disorders may occur as extramedullary disease in multiple myeloma (MM-EMD) or as primary extramedullary plasmocytoma (pEMP)/solitary osseous plasmocytoma (SOP). In this study, we aimed to obtain insights into the molecular mechanisms of extramedullary spread of clonal PC. Methods: Clinical and biological characteristics of 87 patients with MM-EMD (n = 49), pEMP/SOP (n = 20) and classical MM (n = 18) were analyzed by using immunohistochemistry (CXCR4, CD31, CD44 and CD81 staining) and cytoplasmic immunoglobulin staining combined with fluorescence in situ hybridization (cIg-FISH). Results: High expression of CD44, a cell-surface glycoprotein involved in cell-cell interactions, was significantly enriched in MM-EMD (90%) vs. pEMP/SOP (27%) or classical MM (33%) (p < 0.001). In addition, 1q21 amplification by clonal PC occurred at a similar frequency of MM-EMD (33%), pEMP/SOP (57%) and classical MM (44%). Conversely, del(17p13), t(4;14) and t(14;16) were completely absent in pEMP/SOP. Besides this, 1q21 amplification was identified in 64% of not paraskeletal samples from MM-EMD or pEMP compared to 9% of SOP or paraskeletal MM-EMD/pEMP and 44% of classical MM samples, respectively (p = 0.02). Conclusion: Expression of molecules involved in homing and cytogenetic aberrations differ between MM with or without EMD and pEMP/SOP.

Download Full-text

Polymodal Functionality of C. elegans OLL Neurons in Mechanosensation and Thermosensation

Neuroscience Bulletin ◽

10.1007/s12264-021-00629-4 ◽

2021 ◽

Author(s):

Yuedan Fan ◽

Wenjuan Zou ◽

Jia Liu ◽

Umar Al-Sheikh ◽

Hankui Cheng ◽

...

Keyword(s):

Glutamate Receptor ◽

Sensory Neurons ◽

Molecular Mechanisms ◽

Temperature Sensitive ◽

Cold Sensation ◽

Cold Response ◽

C Elegans ◽

Sensory Modalities ◽

A Cell ◽

Bona Fide

AbstractSensory modalities are important for survival but the molecular mechanisms remain challenging due to the polymodal functionality of sensory neurons. Here, we report the C. elegans outer labial lateral (OLL) sensilla sensory neurons respond to touch and cold. Mechanosensation of OLL neurons resulted in cell-autonomous mechanically-evoked Ca2+ transients and rapidly-adapting mechanoreceptor currents with a very short latency. Mechanotransduction of OLL neurons might be carried by a novel Na+ conductance channel, which is insensitive to amiloride. The bona fide mechano-gated Na+-selective degenerin/epithelial Na+ channels, TRP-4, TMC, and Piezo proteins are not involved in this mechanosensation. Interestingly, OLL neurons also mediated cold but not warm responses in a cell-autonomous manner. We further showed that the cold response of OLL neurons is not mediated by the cold receptor TRPA-1 or the temperature-sensitive glutamate receptor GLR-3. Thus, we propose the polymodal functionality of OLL neurons in mechanosensation and cold sensation.

Download Full-text

Molecular organization of mammalian meiotic chromosome axis revealed by expansion STORM microscopy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1902440116 ◽

2019 ◽

Vol 116 (37) ◽

pp. 18423-18428 ◽

Cited By ~ 20

Author(s):

Huizhong Xu ◽

Zhisong Tong ◽

Qing Ye ◽

Tengqian Sun ◽

Zhenmin Hong ◽

...

Keyword(s):

Meiotic Chromosome ◽

Molecular Organization ◽

Homologous Chromosomes ◽

Meiotic Chromosomes ◽

C Terminus ◽

Stochastic Optical Reconstruction Microscopy ◽

Optical Reconstruction ◽

20 Nm ◽

Chromosome Axis

During prophase I of meiosis, chromosomes become organized as loop arrays around the proteinaceous chromosome axis. As homologous chromosomes physically pair and recombine, the chromosome axis is integrated into the tripartite synaptonemal complex (SC) as this structure’s lateral elements (LEs). While the components of the mammalian chromosome axis/LE—including meiosis-specific cohesin complexes, the axial element proteins SYCP3 and SYCP2, and the HORMA domain proteins HORMAD1 and HORMAD2—are known, the molecular organization of these components within the axis is poorly understood. Here, using expansion microscopy coupled with 2-color stochastic optical reconstruction microscopy (STORM) imaging (ExSTORM), we address these issues in mouse spermatocytes at a resolution of 10 to 20 nm. Our data show that SYCP3 and the SYCP2 C terminus, which are known to form filaments in vitro, form a compact core around which cohesin complexes, HORMADs, and the N terminus of SYCP2 are arrayed. Overall, our study provides a detailed structural view of the meiotic chromosome axis, a key organizational and regulatory component of meiotic chromosomes.

Download Full-text

G-protein-coupled receptors signalling at the cell nucleus: an emerging paradigmThis paper is one of a selection of papers published in this Special Issue, entitled The Nucleus: A Cell Within A Cell.

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y05-127 ◽

2006 ◽

Vol 84 (3-4) ◽

pp. 287-297 ◽

Cited By ~ 124

Author(s):

Fernand Gobeil ◽

Audrey Fortier ◽

Tang Zhu ◽

Michela Bossolasco ◽

Martin Leduc ◽

...

Keyword(s):

G Protein ◽

Cell Nucleus ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Cell Metabolism ◽

Hormone Secretion ◽

G Protein Coupled Receptors ◽

A Cell ◽

G Protein Coupled

G-protein-coupled receptors (GPCRs) comprise a wide family of monomeric heptahelical glycoproteins that recognize a broad array of extracellular mediators including cationic amines, lipids, peptides, proteins, and sensory agents. Thus far, much attention has been given towards the comprehension of intracellular signaling mechanisms activated by cell membrane GPCRs, which convert extracellular hormonal stimuli into acute, non-genomic (e.g., hormone secretion, muscle contraction, and cell metabolism) and delayed, genomic biological responses (e.g., cell division, proliferation, and apoptosis). However, with respect to the latter response, there is compelling evidence for a novel intracrine mode of genomic regulation by GPCRs that implies either the endocytosis and nuclear translocation of peripheral-liganded GPCR and (or) the activation of nuclearly located GPCR by endogenously produced, nonsecreted ligands. A noteworthy example of the last scenario is given by heptahelical receptors that are activated by bioactive lipoids (e.g., PGE2 and PAF), many of which may be formed from bilayer membranes including those of the nucleus. The experimental evidence for the nuclear localization and signalling of GPCRs will be reviewed. We will also discuss possible molecular mechanisms responsible for the atypical compartmentalization of GPCRs at the cell nucleus, along with their role in gene expression.

Download Full-text

Factors Controlling Electropermeabilisation of Cell Membranes

Technology in Cancer Research & Treatment ◽

10.1177/153303460200100502 ◽

2002 ◽

Vol 1 (5) ◽

pp. 319-327 ◽

Cited By ~ 8

Author(s):

M. P. Rols ◽

M. Golzio ◽

B. Gabriel ◽

J. Teissié

Keyword(s):

Cell Surface ◽

Electric Field ◽

Pulse Duration ◽

Cell Membranes ◽

Physical Parameters ◽

Local Exchange ◽

Physical Mechanisms ◽

A Cell

Electric field pulses are a new approach for drug and gene delivery for cancer therapy. They induce a localized structural alteration of cell membranes. The associated physical mechanisms are well explained and can be safely controlled. A position dependent modulation of the membrane potential difference is induced when an electric field is applied to a cell. Electric field pulses with an overcritical intensity evoke a local membrane alteration. A free exchange of hydrophilic low molecular weight molecules takes place across the membrane. A leakage of cytosolic metabolites and a loading of polar drugs into the cytoplasm are obtained. The fraction of the cell surface which is competent for exchange is a function of the field intensity. The level of local exchange is strongly controlled by the pulse duration and the number of successive pulses. The permeabilised state is long lived. Its lifetime is under the control of the cumulated pulse duration. Cell viability can be preserved. Gene transfer is obtained but its mechanism is not a free diffusion. Plasmids are electrophoretically accumulated against the permeabilised cell surface and form aggregates due to the field effect. After the pulses, several steps follow: translocation to the cytoplasm, traffic to the nucleus and expression. Molecular structural and metabolic changes in cells remain mostly poorly understood. Nevertheless, while most studies were established on cells in culture ( in vitro), recent experiments show that similar effects are obtained on tissue ( in vivo). Transfer remains controlled by the physical parameters of the electrical treatment.

Download Full-text

Microglia extracellular vesicles: focus on molecular composition and biological function

Biochemical Society Transactions ◽

10.1042/bst20210202 ◽

2021 ◽

Vol 49 (4) ◽

pp. 1779-1790 ◽

Cited By ~ 1

Author(s):

Lorenzo Ceccarelli ◽

Chiara Giacomelli ◽

Laura Marchetti ◽

Claudia Martini

Keyword(s):

Extracellular Vesicles ◽

Molecular Mechanisms ◽

Biological Function ◽

Biological Effects ◽

Genetic Material ◽

Cell Communication ◽

Molecular Composition ◽

Cargo Proteins ◽

A Cell ◽

The Central Nervous System

Extracellular vesicles (EVs) are a heterogeneous family of cell-derived lipid bounded vesicles comprising exosomes and microvesicles. They are potentially produced by all types of cells and are used as a cell-to-cell communication method that allows protein, lipid, and genetic material exchange. Microglia cells produce a large number of EVs both in resting and activated conditions, in the latter case changing their production and related biological effects. Several actions of microglia in the central nervous system are ascribed to EVs, but the molecular mechanisms by which each effect occurs are still largely unknown. Conflicting functions have been ascribed to microglia-derived EVs starting from the neuronal support and ending with the propagation of inflammation and neurodegeneration, confirming the crucial role of these organelles in tuning brain homeostasis. Despite the increasing number of studies reported on microglia-EVs, there is also a lot of fragmentation in the knowledge on the mechanism at the basis of their production and modification of their cargo. In this review, a collection of literature data about the surface and cargo proteins and lipids as well as the miRNA content of EVs produced by microglial cells has been reported. A special highlight was given to the works in which the EV molecular composition is linked to a precise biological function.

Download Full-text

Parallel molecular mechanisms for enzyme temperature adaptation

Science ◽

10.1126/science.aay2784 ◽

2021 ◽

Vol 371 (6533) ◽

pp. eaay2784

Author(s):

Margaux M. Pinney ◽

Daniel A. Mokhtari ◽

Eyal Akiva ◽

Filip Yabukarski ◽

David M. Sanchez ◽

...

Keyword(s):

Molecular Mechanisms ◽

Interaction Networks ◽

Temperature Adaptation ◽

Mechanistic Studies ◽

Sequence Analyses ◽

Evolutionary Mechanisms ◽

Ketosteroid Isomerase ◽

Physical Mechanisms ◽

Bacterial Enzyme ◽

Enzyme Families

The mechanisms that underly the adaptation of enzyme activities and stabilities to temperature are fundamental to our understanding of molecular evolution and how enzymes work. Here, we investigate the molecular and evolutionary mechanisms of enzyme temperature adaption, combining deep mechanistic studies with comprehensive sequence analyses of thousands of enzymes. We show that temperature adaptation in ketosteroid isomerase (KSI) arises primarily from one residue change with limited, local epistasis, and we establish the underlying physical mechanisms. This residue change occurs in diverse KSI backgrounds, suggesting parallel adaptation to temperature. We identify residues associated with organismal growth temperature across 1005 diverse bacterial enzyme families, suggesting widespread parallel adaptation to temperature. We assess the residue properties, molecular interactions, and interaction networks that appear to underly temperature adaptation.

Download Full-text

Microfibrillar-associated protein 5 regulates osteogenic differentiation by modulating the Wnt/β-catenin and AMPK signaling pathways

Molecular Medicine ◽

10.1186/s10020-021-00413-0 ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Haoran Li ◽

Wuling Zhou ◽

Shiwei Sun ◽

Tianlong Zhang ◽

Tieqi Zhang ◽

...

Keyword(s):

Osteogenic Differentiation ◽

Molecular Mechanisms ◽

Control Group ◽

Signaling Proteins ◽

Mrna Levels ◽

Ampk Signaling ◽

Marrow Mesenchymal Stem Cells ◽

Osteogenic Induction ◽

Overexpressing Cell ◽

Gsk 3Β

Abstract Background Dysfunctional osteogenesis of bone marrow mesenchymal stem cells (BMSCs) plays an important role in osteoporosis occurrence and development. However, the molecular mechanisms of osteogenic differentiation remain unclear. This study explored whether microfibrillar-associated protein 5 (MFAP5) regulated BMSCs osteogenic differentiation. Methods We used shRNA or cDNA to knock down or overexpress MFAP5 in C3H10 and MC3T3-E1 cells. AR-S- and ALP-staining were performed to quantify cellular osteogenic differentiation. The mRNA levels of the classical osteogenic differentiation biomarkers Runx2, Col1α1, and OCN were quantified by qRT-PCR. Finally, we employed Western blotting to measure the levels of Wnt/β-catenin and AMPK signaling proteins. Results At days 0, 3, 7, and 14 after osteogenic induction, AR-S- and ALP-staining was lighter in MFAP5 knockdown compared to control cells, as were the levels of Runx2, Col1α1 and OCN. During osteogenesis, the levels of β-catenin, p-GSK-3β, AMPK, and p-AMPK were upregulated, while that of GSK-3β was downregulated, indicating that Wnt/β-catenin and AMPK signaling were activated. The relevant molecules were expressed at lower levels in the knockdown than control group; the opposite was seen for overexpressing cell lines. Conclusions MFAP5 regulates osteogenesis via Wnt/β‑catenin- and AMPK-signaling; MFAP5 may serve as a therapeutic target in patients with osteoporosis.

Download Full-text