The mitotic checkpoint protein hSpindly must be farnesylated at its C terminus in order to be recruited to kinetochores, Moudgil et al. reveal.

Mitotic checkpoint proteins assemble on kinetochores and prevent chromosomes from segregating until they are properly attached to the mitotic spindle. Spindly helps recruit the motor protein dynein to kinetochores so that, once chromosomes are correctly attached, checkpoint proteins can be transported away from the kinetochores and mitosis can proceed. Spindly itself is recruited to kinetochores by the RZZ complex, but the details of this interaction are unknown.

Moudgil et al. found that the C terminus of human Spindly (hSpindly) is farnesylated in vivo. This lipid modification usually promotes proteins’ associations with cell membranes, but mutating hSpindly’s farnesylation site or inhibiting the enzyme farnesyl transferase disrupted hSpindly’s interaction with the RZZ complex and blocked the protein’s recruitment to mitotic kinetochores.

Farnesyl transferase inhibitors (FTIs) were originally developed to impair the function of oncogenic Ras, but they are now thought to inhibit cell division by reducing the farnesylation of one or more mitotic proteins. Two other farnesylated kinetochore proteins, CENP-E and CENP-F, still localized to kinetochores in the presence of FTIs, and knocking down hSpindly produced a prometaphase delay similar to that seen in FTI-treated cells. hSpindly is therefore likely to be the major mitotic target of FTIs. Senior author Gordon Chan now wants to investigate how farnesylation promotes hSpindly’s association with the RZZ complex. The lipid group might induce a conformational change in hSpindly, or it could interact directly with an RZZ subunit.


, et al
J. Cell Biol.

Author notes

Text by Ben Short