Abstract:
: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.
journal_name
Mol Biol Celljournal_title
Molecular biology of the cellauthors
Holland AJ,Reis RM,Niessen S,Pereira C,Andres DA,Spielmann HP,Cleveland DW,Desai A,Gassmann Rdoi
10.1091/mbc.E14-11-1560subject
Has Abstractpub_date
2015-05-15 00:00:00pages
1845-56issue
10eissn
1059-1524issn
1939-4586pii
mbc.E14-11-1560journal_volume
26pub_type
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