Septins are a conserved family of GTP-binding proteins that self-assemble into defined hetero-oligomeric complexes that are able to polymerize to form filaments and other supramolecular arrangements. Septin structures associate with biological membranes by interacting with specific lipids, and are involved in cellular compartmentalization and a variety of membrane remodeling events. Septins are essential in cell division, where they play a number of functional roles, as well as in cellular differentiation Furthermore, septins have been associated with a variety of cancers on the basis of alterations of their expression in solid tumors or translocations in leukemias. Also, expression changes in septins have been implicated in neuropathological conditions, such as Alzheimer's and Parkinson's disease, as well as retinopathies, and mutations in SEPT9 are the cause of hereditary neuralgic amyotrophy (HNA). Yet, little is known about the molecular mechanisms that govern septin organization and function. Further functional characterization of septins is clearly crucial to our understanding of their possible diagnostic, prognostic, and therapeutic applications. For example, what is the nature of the interactions among different septin forms that give rise to polymers with different functional properties? What is the interplay between septin assembly and their interaction with membrane phosphoinositides? What is the organization of septin structures in situ? How do the post- translational modifications that septins undergo influence their properties? How do septins interact with and affect other cellular regulators and cytoskeletal elements? We will address these questions using budding yeast as a model system. Understanding how septin assembly is regulated in this model eukaryotic organism may offer new insights about how aberrant septin structures contribute to malignancy and disease.

Public Health Relevance

Septins are conserved eukaryotic proteins that self-associate, polymerize into filaments, interact with membranes, and are required for membrane remodeling events, from cell division to differentiation. Pronounced up-regulation of certain splice variants f the septin SEPT9 is a hallmark of breast and ovarian cancers and other tumor types. Expression changes in septins have also been associated with neuropathological conditions. Understanding how septin assembly is regulated in our model system will offer new insights about how aberrant septin structures contribute to disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM101314-02
Application #
8600295
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Flicker, Paula F
Project Start
2013-01-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$260,608
Indirect Cost
$89,608
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Finnigan, Gregory C; Thorner, Jeremy (2016) mCAL: A New Approach for Versatile Multiplex Action of Cas9 Using One sgRNA and Loci Flanked by a Programmed Target Sequence. G3 (Bethesda) 6:2147-56
Finnigan, Gregory C; Sterling, Sarah M; Duvalyan, Angela et al. (2016) Coordinate action of distinct sequence elements localizes checkpoint kinase Hsl1 to the septin collar at the bud neck in Saccharomyces cerevisiae. Mol Biol Cell 27:2213-33
Bertin, Aurélie; Nogales, Eva (2016) Characterization of Septin Ultrastructure in Budding Yeast Using Electron Tomography. Methods Mol Biol 1369:113-23
Finnigan, Gregory C; Duvalyan, Angela; Liao, Elizabeth N et al. (2016) Detection of protein-protein interactions at the septin collar in Saccharomyces cerevisiae using a tripartite split-GFP system. Mol Biol Cell 27:2708-25
Bertin, A; Nogales, E (2016) Preparing recombinant yeast septins and their analysis by electron microscopy. Methods Cell Biol 136:21-34
Booth, Elizabeth A; Sterling, Sarah M; Dovala, Dustin et al. (2016) Effects of Bni5 Binding on Septin Filament Organization. J Mol Biol 428:4962-4980
Garcia 3rd, Galo; Finnigan, Gregory C; Heasley, Lydia R et al. (2016) Assembly, molecular organization, and membrane-binding properties of development-specific septins. J Cell Biol 212:515-29
Perez, Adam M; Finnigan, Gregory C; Roelants, Françoise M et al. (2016) Septin-Associated Protein Kinases in the Yeast Saccharomyces cerevisiae. Front Cell Dev Biol 4:119
Booth, E A; Thorner, J (2016) A FRET-based method for monitoring septin polymerization and binding of septin-associated proteins. Methods Cell Biol 136:35-56
Finnigan, Gregory C; Takagi, Julie; Cho, Christina et al. (2015) Comprehensive Genetic Analysis of Paralogous Terminal Septin Subunits Shs1 and Cdc11 in Saccharomyces cerevisiae. Genetics 200:821-41

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