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  • To help ensure the fidelity of mitosis and

    2023-12-01

    To help ensure the fidelity of mitosis and cytokinesis cells monitor these processes and delay cell cycle progression in response to certain defects. The spindle assembly checkpoint (SAC) is a surveillance system which delays Bay 11-7085 onset until a bipolar spindle has been correctly assembled (Lara-Gonzalez et al., 2012, Musacchio and Salmon, 2007). A hallmark of SAC activation is the recruitment of SAC regulators to kinetochores which assemble around centromeric DNA (Lara-Gonzalez et al., 2012, Musacchio and Salmon, 2007) and which provide the connection sites between chromosomes and the mitotic spindle. Much is known about how the SAC is first activated to inhibit anaphase and then, once the spindle is correctly attached to chromosomes, inactivated to allow anaphase and Aurora B kinases are involved in regulating these processes (Campbell and Desai, 2013, Jin and Wang, 2013, Liu et al., 2009, Nigg, 2001, Pinsky et al., 2009, Santaguida et al., 2011, Vanoosthuyse and Hardwick, 2009). However less is known about how cells exit SAC arrest when bipolar spindle formation cannot occur as is the case when microtubules are depolymerized (Gascoigne and Taylor, 2009, Rieder and Maiato, 2004). When spindle function is prevented in A. nidulans, cells exit a mitotic SAC arrest via a regulated process which requires protein synthesis (De Souza et al., 2011, De Souza and Osmani, 2011). This leads to spindle independent mitotic exit (SIME) allowing cells to return to interphase without nuclear division and continue through the cell cycle (De Souza et al., 2011). Such a mechanism might be particularly important in multinucleate hyphae as it allows cells to continue growth when individual nuclei cannot successfully divide. Cells also monitor cytokinesis and delay abscission in response to the presence of lagging chromosomes at the site of abscission. This occurs by related mechanisms called the NoCut pathway in Saccharomyces cerevisiae and the abscission checkpoint in mammalian cells, both of which are regulated by Aurora B kinases (Agromayor and Martin-Serrano, 2013, Norden et al., 2006, Steigemann et al., 2009). Thus Aurora B kinases regulate not only the progression of mitosis and cytokinesis, but are central players in regulating checkpoints ensuring the fidelity of these processes. Mitotic regulation has been studied in several filamentous fungi but is perhaps best understood in A. nidulans in which NIMA, the founding member of the NEK kinase family, was first identified and is essential for mitotic entry (De Souza and Osmani, 2010, Gladfelter, 2006, Osmani et al., 1988, Steinberg and Perez-Martin, 2008). During mitosis NIMA displays a dynamic location to SPBs, chromatin, nuclear pore complexes and the mitotic spindle and has functions at each of these locations (De Souza et al., 2004, De Souza et al., 2000, Govindaraghavan et al., 2014, Larson et al., 2014, Osmani et al., 1988, Shen and Osmani, 2013). Following mitosis NIMA locates to forming septa and then remains at mature septa during interphase (Shen et al., 2014). Although its function at forming septa is not known NIMA’s activity is required to keep septal pores open during interphase whereas loss of NIMA from mature septa during mitosis results in closing of septal pores (Shen et al., 2014). Thus NIMA has functions at both mitotic nuclei and septa. However, despite the likelihood that Aurora B kinases also function at both mitotic nuclei and septa, their location during septation has yet to be described in filamentous fungi. Here we demonstrate that the single essential Aurora kinase of A. nidulans locates sequentially to the kinetochore region and the spindle midzone during mitosis before dispersing. Following mitosis Aurora then reappears in foci and filaments in hyphal regions where septa subsequently form before concentrating in the vicinity of the septal pore. In addition, Aurora displays a unique cell cycle specific location to mature septa following anaphase and resides at this location for a period during the subsequent interphase. We present evidence that rather than being dependent upon the metaphase to anaphase transition the initial location of Aurora to mature septa is dependent upon a timing mechanism following Bay 11-7085 mitotic entry. By generating and utilizing a temperature sensitive allele of A. nidulans Aurora we demonstrate that it is required for SAC activation and successful mitosis. We also show that cellular levels of Aurora increase during a mitotic SAC arrest when Aurora predominantly locates in the region of centromeres and kinetochores. Finally, we find that in addition to cell cycle defects Aurora inactivation leads to cell wall defects and cell lysis indicating an unexpected role for Aurora in cell growth. The data suggest that in addition to its conserved roles Aurora likely has novel functions in filamentous fungi to regulate the SAC, cell growth and perhaps the formation and function of septa.