title: GTSE1 tunes microtubule stability for chromosome alignment and segregation by inhibiting the microtubule depolymerase MCAK.
abstract: The dynamic regulation of microtubules (MTs) during mitosis is critical for accurate chromosome segregation and genome stability. Cancer cell lines with hyperstabilized kinetochore MTs have increased segregation errors and elevated chromosomal instability (CIN), but the genetic defects responsible remain largely unknown. The MT depolymerase MCAK (mitotic centromere-associated kinesin) can influence CIN through its impact on MT stability, but how its potent activity is controlled in cells remains unclear. In this study, we show that GTSE1, a protein found overexpressed in aneuploid cancer cell lines and tumors, regulates MT stability during mitosis by inhibiting MCAK MT depolymerase activity. Cells lacking GTSE1 have defects in chromosome alignment and spindle positioning as a result of MT instability caused by excess MCAK activity. Reducing GTSE1 levels in CIN cancer cell lines reduces chromosome missegregation defects, whereas artificially inducing GTSE1 levels in chromosomally stable cells elevates chromosome missegregation and CIN. Thus, GTSE1 inhibition of MCAK activity regulates the balance of MT stability that determines the fidelity of chromosome alignment, segregation, and chromosomal stability.
authors.affiliation: Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany.
authors.forename: Shweta
authors.initials: S
authors.lastname: Bendre
authors.affiliation: Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany.
authors.forename: Arnaud
authors.identifier: http://orcid.org/0000-0001-5816-4137
authors.initials: A
authors.lastname: Rondelet
authors.affiliation: Department of Biology, McGill University, Montreal H3A 1B1, Quebec, Canada.
authors.forename: Conrad
authors.initials: C
authors.lastname: Hall
authors.affiliation: Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany.
authors.forename: Nadine
authors.identifier: http://orcid.org/0000-0002-2074-9735
authors.initials: N
authors.lastname: Schmidt
authors.affiliation: Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Department of Biology, McGill University, Montreal H3A 1B1, Quebec, Canada.
authors.forename: Gary J
authors.identifier: http://orcid.org/0000-0001-9101-1247
authors.initials: GJ
authors.lastname: Brouhard
authors.affiliation: Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany alex.bird@mpi-dortmund.mpg.de.
authors.forename: Alexander W
authors.identifier: http://orcid.org/0000-0002-1061-0799
authors.initials: AW
authors.lastname: Bird
mesh_terms: D000705:Anaphase; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D020090:Chromosome Segregation; D002877:Chromosomes, Human / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D016547:Kinesins / Q000378:metabolism*; D018386:Kinetochores / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D008938:Mitosis; D011485:Protein Binding; D008941:Spindle Apparatus / Q000378:metabolism
chemical_list: C115080:GTSE1 protein, human; C091489:KIF2C protein, human; D008869:Microtubule-Associated Proteins; C004805:5'-guanylylmethylenebisphosphonate; D006160:Guanosine Triphosphate; D016547:Kinesins