Mitotic regulation is fundamentally important to all eukaryotic life and has medical significance as mitotic defects can lead to aneuploidy and cancer. Mitosis is regulated by a complex interplay of conserved protein kinases but there is a limited understanding of the pertinent kinase substrates and the mechanistic consequences of their phosphorylation. For example, it is unknown how mitotic kinases regulate the stepwise disassembly and reassembly of the nuclear pore complex (NPC) during open mitosis. My laboratory has shown that during the closed mitosis of the model filamentous fungus Aspergillus nidulans, the NPC is partially disassembled with at least 12 NPC proteins (Nups) reversibly dispersing from a core NPC structure. A. nidulans therefore represents a unique and powerful model genetic system in which the NPC is regulated during mitosis in a manner displaying many similarities to human mitotic NPC regulation. Interestingly, A. nidulans An-Nup2 exclusively re-locates to mitotic chromosomes, suggesting a novel mitotic role for this Nup. This proposal aims to: i) Define in detail the reversible changes in the composition of the NPC during mitosis, ii) Characterize how NPC architecture changes when it is disassembled and assembled and relate this to NPC composition and function, iii) Establish how mitotic specific phosphorylation regulates the structure and function of the NPC, and iv) Determine how the localization of An-Nup2 to chromatin helps coordinate NPC disassembly/reassembly with mitotic progression. These studies will help define how the NPC is regulated by kinases during mitosis and how the mitotic regulation of Nups is integrated with mitotic progression.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM042564-20S1
Application #
7911004
Study Section
Nuclear Dynamics and Transport (NDT)
Program Officer
Zatz, Marion M
Project Start
2009-09-07
Project End
2011-02-28
Budget Start
2009-09-07
Budget End
2011-02-28
Support Year
20
Fiscal Year
2009
Total Cost
$252,468
Indirect Cost
Name
Ohio State University
Department
Genetics
Type
Schools of Arts and Sciences
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Suresh, Subbulakshmi; Markossian, Sarine; Osmani, Aysha H et al. (2017) Mitotic nuclear pore complex segregation involves Nup2 in Aspergillus nidulans. J Cell Biol 216:2813-2826
Shukla, Nandini; Osmani, Aysha H; Osmani, Stephen A (2017) Microtubules are reversibly depolymerized in response to changing gaseous microenvironments within Aspergillus nidulans biofilms. Mol Biol Cell 28:634-644
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
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; 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
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
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; 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

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