Patterning of the cell cortex by Rho GTPases

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(4), P. 290 - 308

Published: Jan. 3, 2024

Language: Английский

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Positioning centrioles and centrosomes

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(4)

Published: March 21, 2024

Centrosomes are the primary microtubule organizer in eukaryotic cells. In addition to shaping intracellular network and mitotic spindle, centrosomes responsible for positioning cilia flagella. To fulfill these diverse functions, must be properly located within cells, which requires that they undergo transport. Importantly, centrosome mispositioning has been linked ciliopathies, cancer, infertility. The mechanisms by migrate context dependent. many move via indirect motor transport, whereby centrosomal microtubules engage anchored proteins exert forces on those microtubules, resulting movement. However, some cases, direct or centriole functions as cargo directly binds molecular motors then walk stationary microtubules. this review, we summarize of motility consequences identify key questions remain addressed.

Language: Английский

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Three-dimensional memory of nuclear organization through cell cycles

The Journal of Chemical Physics, Journal Year: 2025, Volume and Issue: 162(6)

Published: Feb. 13, 2025

The genome in the cell nucleus is organized by a dynamic process influenced structural memory from mitosis. In this study, we develop model of human dynamics through cycles extending previously developed whole-genome to cover mitotic phase. With extension, focus on role and cycle organization. simulation progresses mitosis interphase subsequent mitosis, leading successive cycles. During our describes microtubule dynamics, showing how forces orchestrate assembly chromosomes into rosette ring structure at metaphase. explains positioning depends their size metaphase configuration persists dimensions perpendicular division axis, effectively guiding distribution chromosome territories over multiple At onset each G1 phase, phase separation active inactive chromatin domains occurs, A/B compartmentalization. Our cycling simulations show that compartments are unaffected previous consistently established cycle. study highlights interplay between across cycles, providing insights for analyses cellular processes.

Language: Английский

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Microtubule nucleation for spindle assembly: one molecule at a time

Trends in Biochemical Sciences, Journal Year: 2023, Volume and Issue: 48(9), P. 761 - 775

Published: July 21, 2023

Language: Английский

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Mechanisms of minor pole–mediated spindle bipolarization in human oocytes

Science, Journal Year: 2024, Volume and Issue: 385(6711)

Published: Aug. 22, 2024

Spindle bipolarization, the process of a microtubule mass transforming into bipolar spindle, is prerequisite for accurate chromosome segregation. In contrast to mitotic cells, and mechanism spindle bipolarization in human oocytes remains unclear. Using high-resolution imaging more than 1800 oocytes, we revealed typical state multipolar intermediates that form during elucidated underlying this process. We found minor poles formed multiple kinetochore clusters contribute generation intermediates. further determined essential roles HAUS6, KIF11, KIF18A identified mutations these genes infertile patients characterized by oocyte or embryo defects. These results provide insights physiological pathological mechanisms oocytes.

Language: Английский

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19S proteasome loss causes monopolar spindles through ubiquitin-independent KIF11 degradation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 9, 2025

To direct regulated protein degradation, the 26S proteasome recognizes ubiquitinated substrates through its 19S particle and then degrades them in 20S enzymatic core. Despite this close interdependency between subunits, we demonstrate that knockouts from different subcomplexes result distinct highly cellular phenotypes. In particular, depletion of PSMD lid proteins, but not other prevents bipolar spindle assembly during mitosis, resulting a mitotic arrest. We find monopolar phenotype is caused by ubiquitin- independent proteasomal degradation motor KIF11 upon loss proteins. Thus, negative regulation 20S-mediated essential for progression components can function independently outside canonical structure. This work reveals role formation identifies effects on cell cycle control.

Language: Английский

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Functional regulation of the mitotic kinesin HSET by Intraflagellar Transport proteins.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 14, 2025

Abstract HSET is a mitotic kinesin essential for centrosome clustering in cells harboring supernumerary centrosomes. Previous work cellulo revealed physical and functional interaction between intraflagellar transport proteins to control efficient extra subsequent cancer cell proliferation. However, which IFT directly bind whether regulate activity remains unknown. Using reconstituted vitro system combining purified coupled TIRF microscopy approaches, we identified minimal subcomplex made of IFT52/IFT70 binding HSET. We demonstrate that this increases motor its capacity achieve processive runs. also show activation by accounts an increased ability slide microtubules organize dynamic microtubule networks. Overall, reveals can activate provides mechanical explanation how contribute .

Language: Английский

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Diverse microtubule-binding repeats regulate TPX2 activities at distinct locations within the spindle

The Journal of Cell Biology, Journal Year: 2025, Volume and Issue: 224(3)

Published: Jan. 16, 2025

TPX2 is an elongated molecule containing multiple α-helical repeats. It stabilizes microtubules (MTs), promotes MT nucleation, and essential for spindle assembly. However, the molecular basis of how performs these functions remains elusive. Here, we systematically characterized MT-binding activities all modules individually in combinations investigated their respective contributions both vitro cells. We show that contains repeats with opposite preferences “extended” “compacted” tubulin dimer spacing, distinct produce divergent outcomes, making activity highly robust yet tunable. Importantly, a repeat group at C terminus, R8-9, key determinant function. MTs by promoting rescues critical propose model where are spatially regulated via its diverse to accommodate varied locations within spindle. Furthermore, reveal synergy between HURP stabilizing MTs.

Language: Английский

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RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 17, 2025

Abstract SPOUT1/CENP-32 encodes a putative SPOUT RNA methyltransferase previously identified as mitotic chromosome associated protein. depletion leads to centrosome detachment from the spindle poles and misalignment. Aided by gene matching platforms, here we identify 28 individuals with neurodevelopmental delays 21 families bi-allelic variants in detected exome/genome sequencing. Zebrafish spout1/cenp-32 mutants show reduction larval head size concomitant apoptosis likely altered cell cycle progression. In vivo complementation assays zebrafish indicate that missense humans are pathogenic. Crystal structure analysis of reveals most disease-associated located within catalytic domain. Additionally, recurrent reduced activity vitro compromised tethering human cells. Thus, pathogenic cause an autosomal recessive disorder: SpADMiSS ( SPOUT1 Associated Development delay Microcephaly Seizures Short stature) underpinned organization defects consequent segregation errors.

Language: Английский

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The Kinesin-14 Tail: Dual microtubule binding domains drive spindle morphogenesis through tight microtubule cross-linking and robust sliding

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

Proper spindle assembly requires the Kinesin-14 family of motors to organize microtubules (MTs) into bipolar by cross-linking and sliding anti-parallel parallel MTs through their motor tail domains. How they mediate these different activities is unclear. We identified two MT binding domains (MBD1 MBD2) within Xenopus XCTK2 found that MBD1 affinity was weaker than MBD2. Comparable full-length GFP-XCTK2 wild-type protein (GX-WT), containing mutations (GX-MBD1 mut ) stimulated assembly, localized well on spindle, formed narrow spindles. In contrast, GX-MBD2 only partially weakly shorter Biochemical reconstitution demonstrated slid faster GX-WT GX-MBD1 . However, statically cross-linked majority MTs, whereas equally without affecting velocity. These results provide a mechanism which in balance velocity (MBD1) tight (MBD2), are important for localization, basis characterizing how molecular spindle. Spindle organization utilize cross-link slide microtubules. individual moderate both active static not understood.Using biochemical reconstitution, authors determined contains independent microtubule with facilitates sliding, stronger MBD2 mediates cross-linking, assembly.These findings Kinesin-14s differentially control insight can dynamic

Language: Английский

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