HURP controls spindle dynamics to promote proper interkinetochore tension and efficient kinetochore capture.
Through a functional genomic screen for mitotic regulators, we identified hepatoma up-regulated protein (HURP) as a protein that is required for chromosome congression and alignment. In HURP-depleted cells, the persistence of unaligned chromosomes and the reduction of tension across sister kinetochores on aligned chromosomes resulted in the activation of the spindle checkpoint. Although these defects transiently delayed mitotic progression, HeLa cells initiated anaphase without resolution of these deficiencies. This bypass of the checkpoint arrest provides a tumor-specific mechanism for chromosome missegregation and genomic instability. Mechanistically, HURP colocalized with the mitotic spindle in a concentration gradient increasing toward the chromosomes. HURP binds directly to microtubules in vitro and enhances their polymerization. In vivo, HURP stabilizes mitotic microtubules, promotes microtubule polymerization and bipolar spindle formation, and decreases the turnover rate of the mitotic spindle. Thus, HURP controls spindle stability and dynamics to achieve efficient kinetochore capture at prometaphase, timely chromosome congression to the metaphase plate, and proper interkinetochore tension for anaphase initiation.
Wong
Jim
J
Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA.
Fang
Guowei
G
D048750:Cell Nucleus Division / Q000235:genetics / Q000502:physiology; D020869:Gene Expression Profiling; D042822:Genomic Instability; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000378:metabolism* / Q000648:ultrastructure; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000502:physiology*; D008870:Microtubules / Q000378:metabolism / Q000648:ultrastructure; D009363:Neoplasm Proteins / Q000032:analysis / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D008941:Spindle Apparatus / Q000378:metabolism* / Q000648:ultrastructure
C465041:DLGAP5 protein, human; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins