Cell migration and division in amoeboid-like fission yeast

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.Yeast cells are non-motile and are encased in a cell wall that supports high internal turgor pressure. The cell wall is also essential for cellular morphogenesis and cell division. Here, we report unexpected morphogenetic changes in a Schizosaccharomyces pombe mutant defective in cell wall biogenesis. These cells form dynamic cytoplasmic protrusions caused by internal turgor pressure and also exhibit amoeboid-like cell migration resulting from repeated protrusive cycles. The cytokinetic ring responsible for cell division in wild-type yeast often fails in these cells; however, they were still able to divide using a ring-independent alternative mechanism relying on extrusion of the cell body through a hole in the cell wall. This mechanism of cell division may resemble an ancestral mode of division in the absence of cytokinetic machinery. Our findings highlight how a single gene change can lead to the emergence of different modes of cell growth, migration and division.This work was supported by grants to R.R.D. from the Spanish Ministerio de Ciencia e Inovación BFU2010-21310 and P09-CTS-4697 (Proyecto de Excelencia) from La Junta de Andalucia. I.F.-P. was supported by the Spanish Ministerio de Educación (Juan de la Cierva Program). M.B. was supported by the Spanish Ministerio de Educación (FPI Fellowship, BES-2008-004018). J.Z. was supported by grant P09-CTS-4697.Peer Reviewe

Optimización de la levadura de fisión Schizosaccharomyces pombe para su uso en la búsqueda de compuestos antitumorales

La desregulación del ciclo celular puede dar lugar a enfermedades como el cáncer. La levadura Schizosaccharomyces pombe es un organismo modelo que puede usarse para el estudio del ciclo celular y la búsqueda de nuevos fármacos antitumorales. Desgraciadamente, los microtúbulos de la levadura no son sensibles a algunas drogas muy utilizadas como el Taxol. El objetivo de este estudio es optimizar a S. pombe para poder expresar en ella tubulinas humanas en lugar de las endógenas así como analizar mediante modelización molecular los cambios necesarios para hacer a S. pombe sensible. De esta forma podríamos utilizar esta levadura para hacer búsquedas masivas de nuevos compuestos anticancerígenos

Effects of the microtubule nucleator Mto1 on chromosomal movement, DNA repair, and sister chromatid cohesion in fission yeast.

Although the function of microtubules (MTs) in chromosomal segregation during mitosis is well characterized, much less is known about the role of MTs in chromosomal functions during interphase. In the fission yeast Schizosaccharomyces pombe, dynamic cytoplasmic MT bundles move chromosomes in an oscillatory manner during interphase via linkages through the nuclear envelope (NE) at the spindle pole body (SPB) and other sites. Mto1 is a cytoplasmic factor that mediates the nucleation and attachment of cytoplasmic MTs to the nucleus. Here, we test the function of these cytoplasmic MTs and Mto1 on DNA repair and recombination during interphase. We find that mto1Δ cells exhibit defects in DNA repair and homologous recombination (HR) and abnormal DNA repair factory dynamics. In these cells, sister chromatids are not properly paired, and binding of Rad21 cohesin subunit along chromosomal arms is reduced. Our findings suggest a model in which cytoplasmic MTs and Mto1 facilitate efficient DNA repair and HR by promoting dynamic chromosomal organization and cohesion in the nucleus.This work was supported by grants from the Spanish Ministry of Economy and Competitiveness BFU2011-15216-E, P09-CTS-4697, and PGC2018-099849-B-100 to R.R.D.; National Institutes of Health (NIH) R01, GM067690, and GM115185 to F.C.; and NIH grants R01-GM085145 and R35-GM126910 to S.J

Regulation of Fission Yeast Morphogenesis by PP2A Activator pta2

Cell polarization is key for the function of most eukaryotic cells, and regulates cell shape, migration and tissue architecture. Fission yeast, Schizosaccharomyces pombe cells are cylindrical and polarize cell growth to one or both cell tips dependent on the cell cycle stage. Whereas microtubule cytoskeleton contributes to the positioning of the growth sites by delivering polarity factors to the cell ends, the Cdc42 GTPase polarizes secretion via actin-dependent delivery and tethering of secretory vesicles to plasma membrane. How growth is restricted to cell tips and how re-initiation of tip growth is regulated in the cell cycle remains poorly understood. In this work we investigated the function of protein phosphatase type 2A (PP2A) in S. pombe morphogenesis by deleting the evolutionary conserved PTPA-type regulatory subunit that we named pta2. pta2-deleted cells showed morphological defects and altered growth pattern. Consistent with this, actin patches and active Cdc42 were mislocalized in the pta2 deletion. These defects were additive to the lack of Cdc42-GAP Rga4. pta2Δ cells show upregulated Cdc42 activity and pta2 interacts genetically with polarisome components Tea1, Tea4 and For3 leading to complete loss of cell polarity and rounded morphology. Thus, regulation of polarity by PP2A requires the polarisome and involves Pta2-dependent control of Cdc42 activity

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Differential clinical characteristics and prognosis of intraventricular conduction defects in patients with chronic heart failure

Intraventricular conduction defects (IVCDs) can impair prognosis of heart failure (HF), but their specific impact is not well established. This study aimed to analyse the clinical profile and outcomes of HF patients with LBBB, right bundle branch block (RBBB), left anterior fascicular block (LAFB), and no IVCDs. Clinical variables and outcomes after a median follow-up of 21 months were analysed in 1762 patients with chronic HF and LBBB (n = 532), RBBB (n = 134), LAFB (n = 154), and no IVCDs (n = 942). LBBB was associated with more marked LV dilation, depressed LVEF, and mitral valve regurgitation. Patients with RBBB presented overt signs of congestive HF and depressed right ventricular motion. The LAFB group presented intermediate clinical characteristics, and patients with no IVCDs were more often women with less enlarged left ventricles and less depressed LVEF. Death occurred in 332 patients (interannual mortality = 10.8%): cardiovascular in 257, extravascular in 61, and of unknown origin in 14 patients. Cardiac death occurred in 230 (pump failure in 171 and sudden death in 59). An adjusted Cox model showed higher risk of cardiac death and pump failure death in the LBBB and RBBB than in the LAFB and the no IVCD groups. LBBB and RBBB are associated with different clinical profiles and both are independent predictors of increased risk of cardiac death in patients with HF. A more favourable prognosis was observed in patients with LAFB and in those free of IVCDs. Further research in HF patients with RBBB is warranted

A first update on mapping the human genetic architecture of COVID-19

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Interphase microtubule bundles use global cell shape to guide spindle alignment in fission yeast

Correct spindle alignment requires a cell to detect and interpret its global geometry and to communicate this information to the mitotic spindle. In the fission yeast, Schizosaccharomyces pombe, the mitotic spindle is aligned with the longitudinal axis of the rod-shaped cell. Here, using wild-type and cell-shape mutants we investigate the mechanism of initial spindle alignment and show that attachment of interphase microtubules to the spindle pole bodies (SPB), the yeast equivalent of the centrosome, is required to align duplicated SPBs, and thus the mitotic spindle, with the long axis of the cell. In the absence of interphase microtubules or attachment between the microtubules and the SPB, newly formed spindles are randomly oriented. We show that the axis of the mitotic spindle correlates with the axis along which the SPB, as a consequence of interphase microtubule dynamics, oscillates just before mitosis. We propose that cell geometry guides cytoplasmic microtubule alignment, which in turn, determines initial spindle alignment, and demonstrate that a failure of the spindle pre-alignment mechanism results in unequal chromosome segregation when spindle length is reduced.R.R.D. was supported by The Breast Cancer Research Foundation, The Rockefeller University and the Spanish Ministerio de Educación y Ciencia (MEC, Grant # BFU2007-68025)

Spatiotemporal control of spindle disassembly in fission yeast

Maintenance of genomic stability during cell division is one of the most important cellular tasks, and it critically depends on the faithful replication of the genetic material and its equal partitioning into daughter cells, gametes, or spores in the case of yeasts. Defective mitotic spindle assembly and disassembly both result in changes in cellular ploidy that ultimately impinge proliferation fitness and might increase tumor malignancy. Although a great progress has been made in understanding how spindles are assembled to orchestrate chromosome segregation, much less is known about how they are disassembled once completed their function. Here, we review two recently uncovered mechanisms of spindle disassembly that operate at different stages of the fission yeast life cycle.This work was supported by the grants BFU2015-70604 and PGC2018-099849-B-100 to R.R. Daga, from the Ministerio de Economía y Competitividad of the Spanish Government.Peer reviewe