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Baumann, Christoph (2007): Plk1 regulates PICH, a centromere-associated SNF2 family tranlocase that is required for the spindle checkpoint. Dissertation, LMU München: Fakultät für Biologie



To investigate the requirements of mitotic, kinetochore-associated proteins for human chromosome segregation we analyzed the human Ndc80 complex, a core structural component of the outer kinetochore. The Ndc80 complex contains Hec1 and Nuf2 that interact via their N-termini and a smaller subcomplex of Spc24 and Spc25 is linked to Hec1. The complex is required for faithful chromosome congression and the recruitment of several proteins of the outer kinetochore, including the mitotic regulatory kinase Plk1. Pull down experiments with Plk1 identified a novel kinetochore/centromere associated DNA translocase, which we termed PICH, as an interactor of Plk1. The localization of PICH to kinetochores and centromeres is controlled by Plk1; and moreover, Plk1 phosphorylation on PICH negatively regulates its localization / chromatin association. PICH associates with conspicuous threads that persist into anaphase where Topoisomerase II causes their resolution. Moreover, PICH is a novel component of the spindle assembly checkpoint and PICH-dependent checkpoint signaling is likely to be mediated via kinetochore associated Mad2. This study raises questions as to the fate of centromeric DNA in sister chromatid separation and its timing of decatenation. We speculate that this enzyme associates with catenated, centromeric DNA from prometaphase where it may be required to sense the tension between sister kinetochores.