Incorrect regulation of mitosis contributes to progression of cancer and birth defects and discoveries regarding the regulation of mitosis have positively impacted medical research and disease treatments. However, the potential for new insights and further impact on medicine clearly exists. For example, one of the most dramatic yet least understood mitotic processes is the disassembly and reassembly of nuclear pore complexes (NPCs), massive structures providing regulated gateways across the nuclear envelope. How this process is regulated and integrated with other mitotic events potentially involves reversible phosphorylation and our planned experiments will help test this hypothesis. We have shown the NIMA mitotic kinase of Aspergillus nidulans initiates mitosis by promoting NPC disassembly. NIMA is both required and sufficient to promote NPC disassembly and markedly affects mitosis in vertebrate cells suggesting the existence of conserved mitotic substrates. A. nidulans therefore provides a powerful and sophisticated model system in which to understand mitotic regulation of NPCs.
The aims of this application include defining the dynamic mitotic changes in the NPC interactome using affinity purifications and mass spectrometry to identify new NPC proteins (Nups) as well as Nup associated proteins involved in mitotic regulation. In addition we will also focus studies on a new Nup associated protein (AN0162) which contains a transmembrane domain and potentially encodes a fourth transmembrane Nup. Our data suggest that AN0162 has a mitotic function to maintain the peripheral mRNA export factor Gle1 on the nuclear envelope surrounding the nucleolus during mitosis and we will test this hypothesis. Our third focus is on the mitotic functions of Nup2 and its associated proteins NupA, importin 1 and importin 2. Nup2 and NupA translocate from NPCs to chromatin during mitosis when they also become phosphorylated. We will test the hypothesis that NupA mediates the mitotic chromatin location of Nup2, which in turn controls the functions of importin 1 and 2 to regulate mitotic progression. As phosphorylation appears integral to this process, the final aim is to map mitotic phosphorylation sites within Nup2, NupA and importin 2 and then carry out in vivo mutational analysis of the specific phosphorylation sites to determine their function.
How the cell cycle is regulated is of fundamental medical importance because when this regulation goes awry disease states such as birth defects and cancer can result. In addition, many current cancer treatments target different aspects of cell cycle regulation to preferentially kill cells actively passing through the cell cycle. Therefore in terms of public health, the more we understand how the cell cycle is regulated the better positioned we will be to develop drugs against new chemotherapeutic targets to combat diseased states associated with cell cycle defects. The experiments proposed will in addition further our understanding of the NIMA kinase human orthologues of which are involved in specific disease states (kidney disease). Finally, A. nidulans is the model organism of the Aspergilli. Insights to the biology of A. nidulans will impact research on the opportunistic Aspergillus pathogens as well as members being used to generate new pharmacologically active compounds.
|Chemudupati, Mahesh; Osmani, Aysha H; Osmani, Stephen A (2016) A mitotic nuclear envelope tether for Gle1 also impacts nuclear and nucleolar architecture. Mol Biol Cell :|
|Markossian, Sarine; Suresh, Subbulakshmi; Osmani, Aysha H et al. (2015) Nup2 requires a highly divergent partner, NupA, to fulfill functions at nuclear pore complexes and the mitotic chromatin region. Mol Biol Cell 26:605-21|
|Liu, Hui-Lin; Osmani, Aysha H; Osmani, Stephen A (2015) The Inner Nuclear Membrane Protein Src1 Is Required for Stable Post-Mitotic Progression into G1 in Aspergillus nidulans. PLoS One 10:e0132489|
|De Souza, Colin P; Hashmi, Shahr B; Osmani, Aysha H et al. (2014) Application of a new dual localization-affinity purification tag reveals novel aspects of protein kinase biology in Aspergillus nidulans. PLoS One 9:e90911|
|Shen, Kuo-Fang; Osmani, Aysha H; Govindaraghavan, Meera et al. (2014) Mitotic regulation of fungal cell-to-cell connectivity through septal pores involves the NIMA kinase. Mol Biol Cell 25:763-75|
|Larson, Jennifer R; Facemyer, Eric M; Shen, Kuo-Fang et al. (2014) Insights into dynamic mitotic chromatin organization through the NIMA kinase suppressor SonC, a chromatin-associated protein involved in the DNA damage response. Genetics 196:177-95|
|Govindaraghavan, Meera; Anglin, Sarah Lea; Osmani, Aysha H et al. (2014) The Set1/COMPASS histone H3 methyltransferase helps regulate mitosis with the CDK1 and NIMA mitotic kinases in Aspergillus nidulans. Genetics 197:1225-36|
|Govindaraghavan, Meera; Lad, Alisha A; Osmani, Stephen A (2014) The NIMA kinase is required to execute stage-specific mitotic functions after initiation of mitosis. Eukaryot Cell 13:99-109|
|Govindaraghavan, Meera; McGuire Anglin, Sarah Lea; Shen, Kuo-Fang et al. (2014) Identification of interphase functions for the NIMA kinase involving microtubules and the ESCRT pathway. PLoS Genet 10:e1004248|
|De Souza, Colin P; Hashmi, Shahr B; Osmani, Aysha H et al. (2013) Functional analysis of the Aspergillus nidulans kinome. PLoS One 8:e58008|
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