Dispensability of the SAC depends on the time window required by aurora B to ensure chromosome biorientation

Aurora B and the spindle assembly checkpoint (SAC) collaborate to ensure the proper biorientation of chromosomes during mitosis. However, lack of Aurora B activity and inactivation of the SAC have a very different impact on chromosome segregation. This is most evident in Saccharomyces cerevisiae, since in this organism the lack of Aurora B is lethal and leads to severe aneuploidy problems, while the SAC is dispensable under normal growth conditions and mutants in this checkpoint do not show evident chromosome segregation defects. We demonstrate that the efficient repair of incorrect chromosome attachments by Aurora B during the initial stages of spindle assembly in budding yeast determines the lack of chromosome segregation defects in SAC mutants, and propose that the differential time window that Aurora B kinase requires to establish chromosome biorientation is the key factor that determines why some cells are more dependent on a functional SAC than others.Junta de Andalucía CVI-5806Ministerio de Economía y Competitividad BFU2013-43718-PUnión Europea FEDE

Inhibition of the Mitotic Exit Network in Response to Damaged Telomeres

When chromosomal DNA is damaged, progression through the cell cycle is halted to provide the cells with time to repair the genetic material before it is distributed between the mother and daughter cells. In Saccharomyces cerevisiae, this cell cycle arrest occurs at the G2/M transition. However, it is also necessary to restrain exit from mitosis by maintaining Bfa1-Bub2, the inhibitor of the Mitotic Exit Network (MEN), in an active state. While the role of Bfa1 and Bub2 in the inhibition of mitotic exit when the spindle is not properly aligned and the spindle position checkpoint is activated has been extensively studied, the mechanism by which these proteins prevent MEN function after DNA damage is still unclear. Here, we propose that the inhibition of the MEN is specifically required when telomeres are damaged but it is not necessary to face all types of chromosomal DNA damage, which is in agreement with previous data in mammals suggesting the existence of a putative telomere-specific DNA damage response that inhibits mitotic exit. Furthermore, we demonstrate that the mechanism of MEN inhibition when telomeres are damaged relies on the Rad53-dependent inhibition of Bfa1 phosphorylation by the Polo-like kinase Cdc5, establishing a new key role of this kinase in regulating cell cycle progression.España, Ministerio de Ciencia e Innovación BFU2011-2343

Regulation of Spo12 Phosphorylation and Its Essential Role in the FEAR Network

Background: In budding yeast, the protein phosphatase Cdc14 coordinates late mitotic events and triggers exit from mitosis. During early anaphase, Cdc14 is activated by the FEAR network, but how signaling through the FEAR network occurs is poorly understood. Results: We find that the FEAR network component Spo12 is phosphorylated on S118. This phosphorylation is essential for Spo12 function and is restricted to early anaphase, when the FEAR network is active. The anaphase-specific phosphorylation of Spo12 requires mitotic CDKs and depends on the FEAR network components Separase and Slk19. Furthermore, we find that CDC14 is required to maintain Spo12 in the dephosphorylated state prior to anaphase. Conclusions: Our results show that anaphase-specific phosphorylation of Spo12 is essential for FEAR network function and raise the interesting possibility that Cdc14 itself helps to prevent the FEAR network from being prematurely activated.National Institutes of Health (U.S.) (grant GM 056800)Howard Hughes Medical Institute (Investigator

La enseñanza en el máster de abogacía a través del análisis de casos reales de carácter multidisciplinar. Aprendizaje "a partir del estudio de razonamientos parciales temáticos"

Generar blog para publicaciones de alumnos del Máster Abogacía, con "entradas" dirigidas. Habría análisis desde varias disciplinas añadiéndose estudios con enfoque basado en otras áreas de conocimiento, generando interdisciplinariedad

Cell Polarity Determinants Establish Asymmetry in MEN Signaling

14 páginas, 7 figuras.-- El Pdf es la versión manuscrita de autor.Components of the mitotic exit network (MEN), a signaling pathway that triggers exit from mitosis, localize to the spindle pole body (SPB) that migrates into the daughter cell during anaphase but are largely absent from the SPB that remains in the mother cell. Through the analysis of one of the determinants of this asymmetry, Bfa1, we find that the machinery responsible for establishing cell polarity and cytoplasmic microtubules collaborate to establish MEN asymmetry. In cells defective in the Cdc42 signaling pathway or the formin Bni1, Bfa1 localizes to both SPBs. The quantitative analysis of Bfa1 localization further shows that Bfa1 can associate with both SPBs in a transient and highly dynamic fashion, but the protein is stabilized on the SPB that migrates into the daughter cell during anaphase through microtubule-bud cortex interactions. Our results indicate that mother-daughter cell asymmetry determinants establish MEN signaling asymmetry through microtubule-bud cortex interactions.This work was supported by the National Institutes of Health GM056800 to A.A. and a Charles King Trust Postdoctoral Fellowship to F. M.-C. A.A. is also an investigator of the Howard Hughes Medical Institute.Peer reviewe

Inhibición de la salida de mitosis en respuesta a daños en los telómeros

Trabajo presentado en el XXXVI Congreso de la Sociedad Española de Bioquímica y Biología Molecular (SEBBM), celebrado en Madrid del 4 al 6 de septiembre de 2013Peer reviewe

At the poles of cellular aging: spindle microtubule organizing centers as guardians of replicative lifespan

Trabajo presentado como Seminario Plenario en el Barcelona Biomed Seminars, celebrado en Barcelona (España), el 22 de noviembre de 2019In an asymmetric cell division, the newly-generated daughter cell differs from its mother in size, cellular composition or potential to differentiate. The generation of asymmetry during cell division is essential for many microorganisms and play pivotal roles during development and tissue morphogenesis in animals and plant. As such, the asymmetric division of stems cells allows them to self-renew while, at the same time, giving rise to a new cell that enters a particular differentiation program as a consequence of the inheritance of specific cell-fate determinants. The asymmetric distribution of these determinants allows the generation of diverse cell types during development and plays a major role in tissue architecture and morphogenesis. Hence, defects during this process can lead to tissue degeneration or aging due to a reduction in the number of stem cells or, alternatively, to tumorigenesis or tissue hyperplasia if the stem cell pool increases. A fascinating phenomenon associated to asymmetric cell divisions is the differential distribution of the microtubule-organizing centers (MTOCs) that orchestrate mitotic spindle formation. However, despite its evolutionary conservation, the biological meaning of this process was so far unknown. We have generated a powerful genetic system to analyze the consequences of constitutively reversing the MTOC inheritance pattern during the asymmetric cell division of S. cerevisiae, and demonstrate that the differential distribution of these structures is critical in order to preserve cellular lifespan. Using this model, we also shed new light into the mechanisms by which the differential inheritance of these structures contributes to the maintenance of the replicative potential of the cells

A guiding torch at the poles: key roles of the centrosome during asymmetric cell division

Trabajo presentado en Seminario de Investigación. Department of Genetics. University of Cambridge (Reino Unido), celebrado el 12 de mayo de 202

Asymmetric centrosome inheritance and cellular aging

Trabajo presentado en el Mini Symposium Cell Division and Genome Dynamics, celebrado en Salamanca (España), el 16 de julio de 201

Aging at the poles: asymmetric inheritance of spindle microtubule-organizing centers

Trabajo presentado en el 2nd eLife Symposium: Aging, Geroscience and Longevity Symposium, celebrado online el 8 de marzo de 2021. Accesible a través de Youtube: https://www.youtube.com/watch?v=mD0qCPCivzo https://www.youtube.com/watch?v=Ubz-Mi5ff3ISpindle microtubules nucleate from microtubule-organizing centers (MTOCs)located at its poles and known as spindle pole bodies (SPBs) in budding yeast andcentrosomes in higher eukaryotes. The MTOCs duplicate early in the cell cycleand are essential for proper spindle biogenesis, orientation and elongation.Intriguingly, after their duplication, the pre-existent (“old”) and the newlygenerated (“new”) MTOCs can be differentially distributed during certainasymmetric divisions. Work from our laboratory demonstrated thatmaintenance of the pre-established SPB fate plays a pivotal role in preservingbudding yeast replicative lifespan. Specifically, asymmetric SPB inheritance isrequired to ensure normal levels of the Sir2 sirtuin, a widely conserved lifespanmodulator, and to properly distribute functional mitochondria and proteinaggregates, which are selectively retained in the mother cell to reset replicativelifespan in the daughter cell, during cell division. A new study from our group,included in eLife’s Special Issue on “Aging, Geroscience and Longevity”, hasrecently unveil a novel role of Polo-like kinases, a conserved family of key cellcycle regulatory proteins, in the regulation of non-random MTOC distribution.Defects during asymmetric cell divisions have been associated withtumorigenesis, neurodegeneration and developmental problems. Decipheringthe basic mechanisms that regulate these divisions is therefore of utmostrelevance to better understand the causes for these diseases