The clinical interest in farnesyltransferase inhibitors (FTIs) makes it important to understand how these compounds affect cellular processes involving farnesylated proteins. Mitotic abnormalities observed after treatment with FTIs have so far been attributed to defects in the farnesylation of the outer kinetochore proteins CENP-E and CENP-F, which are involved in chromosome congression and spindle assembly checkpoint signaling. Here we identify the cytoplasmic dynein adaptor Spindly as an additional component of the outer kinetochore that is modified by farnesyltransferase (FTase). We show that farnesylation of Spindly is essential for its localization, and thus for the proper localization of dynein and its cofactor dynactin, to prometaphase kinetochores and that Spindly kinetochore recruitment is more severely affected by FTase inhibition than kinetochore recruitment of CENP-E and CENP-F. Molecular replacement experiments show that both Spindly and CENP-E farnesylation are required for efficient chromosome congression. The identification of Spindly as a new mitotic substrate of FTase provides insight into the causes of the mitotic phenotypes observed with FTase inhibitors.
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This work was supported by a Starting Grant from the European Research Council (338410), an EMBO Installation Grant, and funding from the Fundação para a Ciência e a Tecnologia (IF/01015/2013/CP1157/CT0006) to R.G., a W.W. Smith Charitable Trust Research Grant, a March of Dimes Basil O'Conner Scholar Award, a Pew-Stewart Scholar Award, and a Kimmel Scholar Award to A.J.H., grants from the National Institutes of Health to A.D. (GM074215) and D.W.C. (GM29513), and funding from the Ludwig Institute for Cancer Research to A.D. and D.W.C.
Holland, Andrew J.; Reis, Rita M.; Niessen, Sherry; Pereira, Cláudia; Andres, Douglas A.; Spielmann, H. Peter; Cleveland, Don W.; Desai, Arshad; and Gassmann, Reto, "Preventing Farnesylation of the Dynein Adaptor Spindly Contributes to the Mitotic Defects Caused by Farnesyltransferase Inhibitors" (2015). Molecular and Cellular Biochemistry Faculty Publications. 73.