Mammalian Septins Regulate Microtubules, Actin, and the DNA Damage Checkpoint Response
Kremer, Brandon Edward, Department of Microbiology, University of Virginia
Macara, Ian, Department of Microbiology, University of Virginia
Parsons, Thomas, Department of Microbiology, University of Virginia
Septins are a family of GTP binding proteins conserved from yeast to humans. In yeast, septins self-assemble into a ring at the bud neck during cell division. This ring appears to integrate signals from microtubules, the actin cytoskeleton, and the DNA damage repair pathway in an effort to ensure proper cell division. We have found that, in mammalian cells, septins appear to play many of the same roles. Septins form a complex with MAP4, a microtubule associated protein that binds and stabilizes microtubules. Septin binding to MAP4 inhibits its microtubule binding and bundling and decreases microtubule stability. This process is important for proper cell division. Septins also interact with the actin cytoskeleton. Silencing of septin expression by RNA interference causes disintegration of actin stress fibers and changes in cell morphology. This phenotype is induced by the relocalization of the adapter protein NCK from the cytoplasm to the nucleus. NCK is carried into the nucleus by Suppressor of Cytokine Signaling-7 (SOCS7), a septin binding, nucleocytoplasmic shuttling protein that contains both nuclear import and export signals. The cytoplasmic localization of both NCK and SOCS7 relies on intact septin architecture. Intriguingly, DNA damage induces changes to septins and the actin cytoskeleton, and both SOCS7 and NCK accumulate in the nucleus. NCK expression is necessary for DNA damage-induced cell cycle checkpoint arrest, as well as for full activation of the checkpoint proteins Chk2 and p53. Furthermore, SOCS7 is ii essential for this process. SOCS7-depleted cells do not exhibit NCK relocalization in response to UV irradiation and do not efficiently activate Chk2. These data, taken together, demonstrate that mammalian septins play a role in the regulation of microtubules, actin, and the DNA damage response. Further study will be needed to determine the mechanisms of septin-SOCS7 and septinMAP4 interactions, as well as determine the in vivo consequences of deficiencies within these pathways.
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PHD (Doctor of Philosophy)
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