bims-micesi 2023-10-22 papers

Issue of 2023‒10‒22
six papers selected by
Valentina Piano, Uniklinik Köln

iScience. 2023 Oct 20. 26(10): 108011

A Haspin-ARHGAP11A axis regulates epithelial morphogenesis through Rho-ROCK dependent modulation of LIMK1-Cofilin.

Roberto Quadri, Giuseppe Rotondo, Sarah Sertic, Sara Pozzi, Maria Chiara dell'Oca, Luisa Guerrini, Marco Muzi-Falconi.

Throughout mitosis, a plethora of processes must be efficiently concerted to ensure cell proliferation and tissue functionality. The mitotic spindle does not only mediate chromosome segregation, but also defines the axis of cellular division, thus determining tissue morphology. Functional spindle orientation relies on precise actin dynamics, shaped in mitosis by the LIMK1-Cofilin axis. The kinase Haspin acts as a guardian of faithful chromosome segregation that ensures amphitelic chromosome attachment and prevents unscheduled cohesin cleavage. Here, we report an unprecedented role for Haspin in the determination of spindle orientation in mitosis. We show that, during mitosis, Haspin regulates Rho-ROCK activity through ARHGAP11A, a poorly characterized GAP, and that ROCK is in turn responsible for the mitotic activation of LIMK1 and stabilization of the actin cytoskeleton, thus supporting a functional spindle orientation. By exploiting 3D cell cultures, we show that this pathway is pivotal for the establishment of a morphologically functional tissue.

Keywords: Cell biology; Molecular biology

DOI: https://doi.org/10.1016/j.isci.2023.108011

Phys Rev E. 2023 Sep;108(3-1): 034401

Microtubule search-and-capture model evaluates the effect of chromosomal volume conservation on spindle assembly during mitosis.

Pinaki Nayak, Saptarshi Chatterjee, Raja Paul.

Variation in the chromosome numbers can arise from the erroneous mitosis or fusion and fission of chromosomes. While the mitotic errors lead to an increase or decrease in the overall chromosomal substance in the daughter cells, fission and fusion keep this conserved. Variations in chromosome numbers are assumed to be a crucial driver of speciation. For example, the members of the muntjac species are known to have very different karyotypes with the chromosome numbers varying from 2n=70+3B in the brown brocket deer to 2n=46 in the Chinese muntjac and 2n=6/7 in the Indian muntjac. The chromosomal content in the nucleus of these closely related mammals is roughly the same and various chromosome fusion and fission pathways have been suggested as the evolution process of these karyotypes. Similar trends can also be found in lepidoptera and yeast species which show a wide variation of chromosome numbers. The effect of chromosome number variation on the spindle assembly time and accuracy is still not properly addressed. We computationally investigate the effect of conservation of the total chromosomal substance on the spindle assembly during prometaphase. Our results suggest that chromosomal fusion pathways aid the microtubule-driven search and capture of the kinetochore in cells with monocentric chromosomes. We further report a comparative analysis of the site and percentage of amphitelic captures, dependence on cell shape, and position of the kinetochore in respect to chromosomal volume partitioning.

DOI: https://doi.org/10.1103/PhysRevE.108.034401

Front Cell Dev Biol. 2023 ;11 1276532

Novel regulation on the mitotic checkpoint revealed by knocking out CDC20.

Ying Wang, Yuqing Zhang, Gang Zhang.

Keywords: CRISPR; CRY box; Cdc20; SAC; translation reinitiation

DOI: https://doi.org/10.3389/fcell.2023.1276532

Chromosome Res. 2023 Oct 21. 31(4): 31

Permission to pass: on the role of p53 as a gatekeeper for aneuploidy.

Joana F Marques, Geert J P L Kops.

Aneuploidy-the karyotype state in which the number of chromosomes deviates from a multiple of the haploid chromosome set-is common in cancer, where it is thought to facilitate tumor initiation and progression. However, it is poorly tolerated in healthy cells: during development and tissue homeostasis, aneuploid cells are efficiently cleared from the population. It is still largely unknown how cancer cells become, and adapt to being, aneuploid. P53, the gatekeeper of the genome, has been proposed to guard against aneuploidy. Aneuploidy in cancer genomes strongly correlates with mutations in TP53, and p53 is thought to prevent the propagation of aneuploid cells. Whether p53 also participates in preventing the mistakes in cell division that lead to aneuploidy is still under debate. In this review, we summarize the current understanding of the role of p53 in protecting cells from aneuploidy, and we explore the consequences of functional p53 loss for the propagation of aneuploidy in cancer.

Keywords: Aneuploidy; Cancer; Chromosomal instability; p53

DOI: https://doi.org/10.1007/s10577-023-09741-9

J Biol Chem. 2023 Oct 12. pii: S0021-9258(23)02368-2. [Epub ahead of print] 105340

The microtubule quartet protein SNAP1 in Trypanosoma brucei facilitates flagellum and cell division plane positioning by promoting basal body segregation.

Thiago Souza Onofre, Kieu T M Pham, Qing Zhou, Ziyin Li.

The unicellular protozoan Trypanosoma brucei has a single flagellum that is involved in cell motility, cell morphogenesis, and cell division. Inheritance of the newly assembled flagellum during the cell cycle requires its correct positioning, which depends on the faithful duplication and segregation of multiple flagellum-associated cytoskeletal structures, including the basal body, the flagellum attachment zone, and the hook complex. Along the flagellum attachment zone sites a set of four microtubules termed the microtubule quartet (MtQ), whose molecular function remains enigmatic. We recently reported that the MtQ-localized protein NHL1 interacts with the microtubule-binding protein TbSpef1 and regulates flagellum inheritance by promoting basal body rotation and segregation. Here, we identified a TbSpef1- and NHL1-associated protein named SNAP1, which co-localizes with NHL1 and TbSpef1 at the proximal portion of the MtQ, depends on TbSpef1 for its localization, and is required for NHL1 localization to the MtQ. Knockdown of SNAP1 impairs the rotation and segregation of the basal body, the elongation of the flagellum attachment zone filament, and the positioning of the newly assembled flagellum, thereby causing a mis-placement of the cell division plane, a halt in cleavage furrow ingression, and an inhibition of cytokinesis completion. Together, these findings uncover a coordinating role of SNAP1 with TbSpef1 and NHL1 in facilitating flagellum positioning and cell division plane placement for the completion of cytokinesis.

Keywords: Trypanosoma brucei; cytokinesis; flagellum inheritance; hook complex; microtubule quartet

DOI: https://doi.org/10.1016/j.jbc.2023.105340

Cell Rep. 2023 Oct 14. pii: S2211-1247(23)01247-0. [Epub ahead of print]42(10): 113235

TERRA R-loops connect and protect sister telomeres in mitosis.

Samantha Sze, Amit Bhardwaj, Priyanka Fnu, Kameron Azarm, Rachel Mund, Katherine Ring, Susan Smith.

Resolution of cohesion between sister telomeres in human cells depends on TRF1-mediated recruitment of the polyADP-ribosyltransferase tankyrase to telomeres. In human aged cells, due to insufficient recruitment of TRF1/tankyrase to shortened telomeres, sisters remain cohered in mitosis. This persistent cohesion plays a protective role, but the mechanism by which sisters remain cohered is not well understood. Here we show that telomere repeat-containing RNA (TERRA) holds sister telomeres together through RNA-DNA hybrid (R-loop) structures. We show that a tankyrase-interacting partner, the RNA-binding protein C19orf43, is required for repression of TERRA R-loops. Persistent telomere cohesion in C19orf43-depleted cells is counteracted by RNaseH1, confirming that RNA-DNA hybrids hold sisters together. Consistent with a protective role for persistent telomere cohesion, depletion of C19orf43 in aged cells reduces DNA damage and delays replicative senescence. We propose that the inherent inability of shortened telomeres to recruit R-loop-repressing machinery permits a controlled onset of senescence.

Keywords: C19orf43; CP: Molecular biology; R-Loops; RNA-DNA hybrids; RNaseH; TERRA; TRF1; cohesion; senescence; tankyrase; telomeres

DOI: https://doi.org/10.1016/j.celrep.2023.113235