title: TRIP13PCH-2 promotes Mad2 localization to unattached kinetochores in the spindle checkpoint response.
abstract: The spindle checkpoint acts during cell division to prevent aneuploidy, a hallmark of cancer. During checkpoint activation, Mad1 recruits Mad2 to kinetochores to generate a signal that delays anaphase onset. Yet, whether additional factors contribute to Mad2's kinetochore localization remains unclear. Here, we report that the conserved AAA+ ATPase TRIP13(PCH-2) localizes to unattached kinetochores and is required for spindle checkpoint activation in Caenorhabditis elegans. pch-2 mutants effectively localized Mad1 to unattached kinetochores, but Mad2 recruitment was significantly reduced. Furthermore, we show that the C. elegans orthologue of the Mad2 inhibitor p31(comet)(CMT-1) interacts with TRIP13(PCH-2) and is required for its localization to unattached kinetochores. These factors also genetically interact, as loss of p31(comet)(CMT-1) partially suppressed the requirement for TRIP13(PCH-2) in Mad2 localization and spindle checkpoint signaling. These data support a model in which the ability of TRIP13(PCH-2) to disassemble a p31(comet)/Mad2 complex, which has been well characterized in the context of checkpoint silencing, is also critical for spindle checkpoint activation.
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Nelson
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064.
authors.forename: Tom
authors.initials: T
authors.lastname: Hwang
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064.
authors.forename: Pin-Hsi
authors.initials: PH
authors.lastname: Chen
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064 nbhalla@ucsc.edu.
authors.forename: Needhi
authors.initials: N
authors.lastname: Bhalla
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000822:Animal Husbandry / Q000379:methods; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D018386:Kinetochores / Q000378:metabolism*; D064246:Mad2 Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D008941:Spindle Apparatus / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C412839:MDF-1 protein, C elegans; D064246:Mad2 Proteins; D009687:Nuclear Proteins; C000599595:PCH-2 protein, C elegans; D000251:Adenosine Triphosphatases