GRK 1739 - Research Projects
Project 5 An old passenger as a new driver: Defining Survivin’s role as a link between replication fork dynamics and radiation response
Prof. Dr. phil. nat. Shirley Knauer
Dept. of Molecular Biology II,
University of Duisburg-Essen
Pre- as well as clinical evidence supports Survivin’s relevance as a tumor radiation-resistance factor. In the previous funding period, we showed that chemico-genetic survivin depletion by RNAi or identified small molecule survivin inhibitors resulted in reduced DNA repair and increased tumors’ radiosensitivity. Mechanistically, albeit radiation did not affect Survivin’s nucleo-cytoplasmic transport, it triggered the formation of unique survivin nuclear foci in centromeric heterochromatin not co-localizing with DNA repair factors. Survivin nuclear foci also contained the CPC members Aurora-B kinase, Borealin and INCENP, but not other kinetochore-residing proteins. Interestingly, Survivin foci were also detectable during S phase, and Survivin depletion reduced DNA replication fork dynamics. Our recent data strongly suggest a previously unknown function for Survivin/(CPC members), linking DNA replication with cellular radiation response. Consequently, we now analyze how this contributes to radiation-resistance and define functionally relevant interaction partners.
Unruhe B, Schröder E, Wünsch D, Knauer SK. An old flame never dies - Survivin in cancer and cellular senescence. Gerontology 2016;62:173-81.
Althoff K, Lindner S, Odersky A, Mestdagh P, Beckers A, Karczewski S, Molenaar J, Bohrer A, Knauer SK, Speleman F, Epple M, Kozlova D, Yoon S, Baek K, Vandesompele J, Eggert A, Schramm A, Schulte J. miR-542-3p exerts tumor suppressive functions in neuroblastoma by downregulating Survivin. Int J Cancer 2015;136:1308-20.
Knauer SK, Unruhe B, Karczewski S, Hecht R, Fetz V, Bier C, Friedl S, Habtemichael N, Heinrich U-R, Stauber RH. Functional characterization of novel mutations affecting survivin (BIRC5)-mediated therapy resistance in head and neck cancer patients. Human Mutation 2013;34:395-404.
Tenzer S, Docter D, Kuharev J, Musyanovych A, Fetz V, Hecht R, Schlenk F, Fischer D, Kiouptsi K, Reinhardt C, Landfester K, Schild H, Maskos M, Knauer SK, Stauber RH. Rapid formation of plasma protein corona critically affects nanoparticle pathophysiology. Nature Nanotechnology 2013;8:772-81.
Knauer SK, Bier C, Habtemichael N, Stauber RH. The Survivin-Crm1 interaction is essential for chromosomal passenger complex localization and function. EMBO Rep 2006;7:1259-1265.