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International Journal of Molecular... Jun 2022Microtubules are major components of the cytoskeleton that play important roles in cellular processes such as intracellular transport and cell division. In recent years,... (Review)
Review
Microtubules are major components of the cytoskeleton that play important roles in cellular processes such as intracellular transport and cell division. In recent years, it has become evident that microtubule networks play a role in genome maintenance during interphase. In this review, we highlight recent advances in understanding the role of microtubule dynamics in DNA damage response and repair. We first describe how DNA damage checkpoints regulate microtubule organization and stability. We then highlight how microtubule networks are involved in the nuclear remodeling following DNA damage, which leads to changes in chromosome organization. Lastly, we discuss how microtubule dynamics participate in the mobility of damaged DNA and promote consequent DNA repair. Together, the literature indicates the importance of microtubule dynamics in genome organization and stability during interphase.
Topics: Cell Nucleus; Centrosome; Cytoskeleton; DNA Damage; Interphase; Microtubules
PubMed: 35805981
DOI: 10.3390/ijms23136986 -
Cell Oct 2019The axoneme of motile cilia is the largest macromolecular machine of eukaryotic cells. In humans, impaired axoneme function causes a range of ciliopathies. Axoneme...
The axoneme of motile cilia is the largest macromolecular machine of eukaryotic cells. In humans, impaired axoneme function causes a range of ciliopathies. Axoneme assembly, structure, and motility require a radially arranged set of doublet microtubules, each decorated in repeating patterns with non-tubulin components. We use single-particle cryo-electron microscopy to visualize and build an atomic model of the repeating structure of a native axonemal doublet microtubule, which reveals the identities, positions, repeat lengths, and interactions of 38 associated proteins, including 33 microtubule inner proteins (MIPs). The structure demonstrates how these proteins establish the unique architecture of doublet microtubules, maintain coherent periodicities along the axoneme, and stabilize the microtubules against the repeated mechanical stress induced by ciliary motility. Our work elucidates the architectural principles that underpin the assembly of this large, repetitive eukaryotic structure and provides a molecular basis for understanding the etiology of human ciliopathies.
Topics: Axoneme; Cell Movement; Cilia; Ciliopathies; Cryoelectron Microscopy; Humans; Microtubule Proteins; Microtubules; Stress, Mechanical
PubMed: 31668805
DOI: 10.1016/j.cell.2019.09.030 -
Current Opinion in Cell Biology Jun 2024Cells generate a highly diverse microtubule network to carry out different activities. This network is comprised of distinct tubulin isotypes, tubulins with different... (Review)
Review
Cells generate a highly diverse microtubule network to carry out different activities. This network is comprised of distinct tubulin isotypes, tubulins with different post-translational modifications, and many microtubule-based structures. Defects in this complex system cause numerous human disorders. However, how different microtubule subtypes in this network regulate cellular architectures and activities remains largely unexplored. Emerging tools such as photosensitive pharmaceuticals, chemogenetics, and optogenetics enable the spatiotemporal manipulation of structures, dynamics, post-translational modifications, and cross-linking with actin filaments in target microtubule subtypes. This review summarizes the design rationale and applications of these new approaches and aims to provide a roadmap for researchers navigating the intricacies of microtubule dynamics and their post-translational modifications in cellular contexts, thereby opening new avenues for therapeutic interventions.
Topics: Microtubules; Humans; Animals; Protein Processing, Post-Translational; Optogenetics; Tubulin
PubMed: 38640790
DOI: 10.1016/j.ceb.2024.102360 -
Cold Spring Harbor Perspectives in... Jul 2015A metaphase spindle is a complex structure consisting of microtubules and a myriad of different proteins that modulate microtubule dynamics together with chromatin and... (Review)
Review
A metaphase spindle is a complex structure consisting of microtubules and a myriad of different proteins that modulate microtubule dynamics together with chromatin and kinetochores. A decade ago, a full description of spindle formation and function seemed a lofty goal. Here, we describe how work in the last 10 years combining cataloging of spindle components, the characterization of their biochemical activities using single-molecule techniques, and theory have advanced our knowledge. Taken together, these advances suggest that a full understanding of spindle assembly and function may soon be possible.
Topics: Animals; Metaphase; Microtubule-Associated Proteins; Microtubules; Models, Biological; Spindle Apparatus; Xenopus laevis
PubMed: 26134313
DOI: 10.1101/cshperspect.a015784 -
Current Opinion in Cell Biology Feb 2020Microtubules control cell architecture by serving as a scaffold for intracellular transport, signaling, and organelle positioning. Microtubules are intrinsically... (Review)
Review
Microtubules control cell architecture by serving as a scaffold for intracellular transport, signaling, and organelle positioning. Microtubules are intrinsically polarized, and their orientation, density, and post-translational modifications both respond and contribute to cell polarity. Animal cells that can rapidly reorient their polarity axis, such as fibroblasts, immune cells, and cancer cells, contain radially organized microtubule arrays anchored at the centrosome and the Golgi apparatus, whereas stably polarized cells often acquire non-centrosomal microtubule networks attached to the cell cortex, nucleus, or other structures. Microtubule density, longevity, and post-translational modifications strongly depend on the dynamics of their plus ends. Factors controlling microtubule plus-end dynamics are often part of cortical assemblies that integrate cytoskeletal organization, cell adhesion, and secretion and are subject to microtubule-dependent feedback regulation. Finally, microtubules can mechanically contribute to cell asymmetry by promoting cell elongation, a property that might be important for cells with dense microtubule arrays growing in soft environments.
Topics: Animals; Cell Polarity; Humans; Microtubules
PubMed: 31739264
DOI: 10.1016/j.ceb.2019.10.004 -
Archives of Biochemistry and Biophysics Apr 2012With the functional characterization of proteins advancing at fast pace, the notion that one protein performs different functions - often with no relation to each other... (Review)
Review
With the functional characterization of proteins advancing at fast pace, the notion that one protein performs different functions - often with no relation to each other - emerges as a novel principle of how cells work. Molecular motors are no exception to this new development. Here, we provide an account on recent findings revealing that microtubule motors are multifunctional proteins that regulate many cellular processes, in addition to their main function in transport. Some of these functions rely on their motor activity, but others are independent of it. Of the first category, we focus on the role of microtubule motors in organelle biogenesis, and in the remodeling of the cytoskeleton, especially through the regulation of microtubule dynamics. Of the second category, we discuss the function of microtubule motors as static anchors of the cargo at the destination, and their participation in regulating signaling cascades by modulating interactions between signaling proteins, including transcription factors. We also review atypical forms of transport, such as the cytoplasmic streaming in the oocyte, and the movement of cargo by microtubule fluctuations. Our goal is to provide an overview of these unexpected functions of microtubule motors, and to incite future research in this expanding field.
Topics: Animals; Humans; Microtubules; Models, Biological; Models, Chemical; Models, Molecular; Molecular Motor Proteins; Structure-Activity Relationship
PubMed: 22306515
DOI: 10.1016/j.abb.2011.12.029 -
ELife Dec 2021Sjögren's syndrome nuclear autoantigen-1 (SSNA1/NA14) is a microtubule-associated protein with important functions in cilia, dividing cells, and developing neurons....
Sjögren's syndrome nuclear autoantigen-1 (SSNA1/NA14) is a microtubule-associated protein with important functions in cilia, dividing cells, and developing neurons. However, the direct effects of SSNA1 on microtubules are not known. We employed in vitro reconstitution with purified proteins and TIRF microscopy to investigate the activity of human SSNA1 on dynamic microtubule ends and lattices. Our results show that SSNA1 modulates all parameters of microtubule dynamic instability-slowing down the rates of growth, shrinkage, and catastrophe, and promoting rescue. We find that SSNA1 forms stretches along growing microtubule ends and binds cooperatively to the microtubule lattice. Furthermore, SSNA1 is enriched on microtubule damage sites, occurring both naturally, as well as induced by the microtubule severing enzyme spastin. Finally, SSNA1 binding protects microtubules against spastin's severing activity. Taken together, our results demonstrate that SSNA1 is both a potent microtubule-stabilizing protein and a novel sensor of microtubule damage; activities that likely underlie SSNA1's functions on microtubule structures in cells.
Topics: Autoantigens; Cell Line; Humans; Microtubule-Associated Proteins; Microtubules; Nuclear Proteins; Spastin
PubMed: 34970964
DOI: 10.7554/eLife.67282 -
Annual Review of Physiology Feb 2022Microtubules are essential cytoskeletal elements found in all eukaryotic cells. The structure and composition of microtubules regulate their function, and the dynamic... (Review)
Review
Microtubules are essential cytoskeletal elements found in all eukaryotic cells. The structure and composition of microtubules regulate their function, and the dynamic remodeling of the network by posttranslational modifications and microtubule-associated proteins generates diverse populations of microtubules adapted for various contexts. In the cardiomyocyte, the microtubules must accommodate the unique challenges faced by a highly contractile, rigidly structured, and long-lasting cell. Through their canonical trafficking role and positioning of mRNA, proteins, and organelles, microtubules regulate essential cardiomyocyte functions such as electrical activity, calcium handling, protein translation, and growth. In a more specialized role, posttranslationally modified microtubules form load-bearing structures that regulate myocyte mechanics and mechanotransduction. Modified microtubules proliferate in cardiovascular diseases, creating stabilized resistive elements that impede cardiomyocyte contractility and contribute to contractile dysfunction. In this review, we highlight the most exciting new concepts emerging from recent studies into canonical and noncanonical roles of cardiomyocyte microtubules.
Topics: Cytoskeleton; Humans; Mechanotransduction, Cellular; Microtubules; Myocytes, Cardiac; Protein Processing, Post-Translational
PubMed: 34614374
DOI: 10.1146/annurev-physiol-062421-040656 -
Experimental Biology and Medicine... Nov 2019Microtubules are cytoskeletal elements known as drivers of directed cell migration, vesicle and organelle trafficking, and mitosis. In this review, we discuss new... (Review)
Review
UNLABELLED
Microtubules are cytoskeletal elements known as drivers of directed cell migration, vesicle and organelle trafficking, and mitosis. In this review, we discuss new research in the lens that has shed light into further roles for stable microtubules in the process of development and morphogenesis. In the lens, as well as other systems, distinct roles for characteristically dynamic microtubules and stabilized populations are coming to light. Understanding the mechanisms of microtubule stabilization and the associated microtubule post-translational modifications is an evolving field of study. Appropriate cellular homeostasis relies on not only one cytoskeletal element, but also rather an interaction between cytoskeletal proteins as well as other cellular regulators. Microtubules are key integrators with actin and intermediate filaments, as well as cell–cell junctional proteins and other cellular regulators including myosin and RhoGTPases to maintain this balance.
IMPACT STATEMENT
The role of microtubules in cellular functioning is constantly expanding. In this review, we examine new and exciting fields of discovery for microtubule’s involvement in morphogenesis, highlight our evolving understanding of differential roles for stabilized versus dynamic subpopulations, and further understanding of microtubules as a cellular integrator.
Topics: Animals; Humans; Microtubules; Morphogenesis
PubMed: 31387376
DOI: 10.1177/1535370219867296 -
European Journal of Cancer (Oxford,... Jan 2013Combined radiochemotherapy treatment modalities are in use for many indications and therefore of high interest. Even though a combined modality in clinical use is often... (Review)
Review
Combined radiochemotherapy treatment modalities are in use for many indications and therefore of high interest. Even though a combined modality in clinical use is often driven by pragmatic aspects, mechanistic preclinical-based concepts of interaction are of importance in order to translate and implement an optimal combination and scheduling of two modalities into the clinics. The use of microtubule stabilising agents is a promising strategy for anti-cancer therapy as a part of combined treatment modality with ionising radiation. Traditionally, microtubule targeting agents are classified as cytotoxic chemotherapeutics and are mostly used in a maximally tolerated dose regimen. Apart from direct cytotoxicity and similar to mechanisms of molecular targeting agents, microtubule stabilising agents interfere with multiple cellular processes, which can be exploited as part of combined treatment modalities. Recent preclinical investigations on the combination of ionising radiation and microtubule stabilising agents reveal new mechanistic interactions on the cellular and tumour level and elucidate the supra-additive tumour response observed particularly in vivo. The major focus on the mechanism of interaction was primarily based on radiosensitisation due to cell cycle arrest in the most radiosensitive G2/M-phase of the cell cycle. However, other mechanisms of interaction such as reoxygenation and direct as well as indirect endothelial damage have also been identified. In this review we summarise and allocate additive and synergistic effects induced by the combined treatment of clinically relevant microtubule stabilising agents and ionising radiation along a described radiobiological framework encompassing distinct mechanisms relevant for exploiting the combination of drugs and ionising radiation.
Topics: Animals; Chemoradiotherapy; Humans; Microtubules; Neoplasms; Radiation-Sensitizing Agents
PubMed: 22683167
DOI: 10.1016/j.ejca.2012.05.008