IDENTIFYING THE ROLE OF THE ZW10/ROD COMPLEX IN MITOTIC CHECKPOINT SIGNALING

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The mitotic checkpoint is the primary mechanism for ensuring that each new cell receives one copy of every chromosome. One complex implicated in the establishment of this checkpoint is Zeste White 10/Rough Deal (ZW10/Rod) [1,2]. Both gene products were originally identified in flies as mutants that displayed aberrant mitotic progression [3,4], and subsequent approaches in flies and human cells implicated the complex in the mitotic checkpoint. Unlike most of the other checkpoint components (see [5] for review); however, it is entirely unclear what role this complex plays in the generation of the checkpoint signal, and neither has any recognizable protein domains in their primary seqeunce. Possible clues come from studies that have identified binding partners. p50 dynamitin, a component of the dynactin complex, is a binding partner of ZW10; the localization of dynein to the kinetochores during mitoses and the subsequent poleward movement of the chromosomes during anaphase are dependent on ZW10 and Rod [6,7]. However, dynein inhibition has the exact opposite effect on mitotic checkpoint activity compared to ZW10 inhibition: dynein inhibition chronically activates the checkpoint, whereas ZW10 inhibition abrogates it.