title: The Deubiquitinase USP37 Regulates Chromosome Cohesion and Mitotic Progression.
abstract: A bipolar mitotic spindle facilitates the equal segregation of chromosomes to two daughter cells. To achieve bipolar attachment of microtubules to kinetochores of sister chromatids, chromatids must remain paired after replication. This cohesion is mediated by the conserved cohesin complex comprised of SMC1, SMC3, SCC1, and either SA1 or SA2 in humans. Because defects in spindle assembly or sister chromatid cohesion can lead to aneuploidy in daughter cells, proper regulation of these processes is essential for fidelity in chromosome segregation. In an RNAi screen for regulators of spindle assembly, we identify the deubiquitinase USP37 as a regulator of mitotic progression, centrosome integrity, and chromosome alignment. USP37 associates with cohesin and contributes to sister chromatid resolution. Cohesion defects are rescued by expression of an RNAi-resistant USP37, but not the catalytically impaired USP37(C350A) mutant. Further, USP37 associates with WAPL, a negative regulator of cohesion necessary for cohesin release in prophase, in a manner dependent on USP37's second and third ubiquitin-interacting motifs. Depletion of USP37 reduces the stability of chromatin-associated WAPL and increases the fraction of WAPL that is more heavily ubiquitylated in mitosis. Consistently, overexpression of USP37(C350A) results in increased modification of WAPL, and addition of purified USP37(WT), but not USP37(C350A), to WAPL immunoprecipitates results in a reduction of ubiquitylated products. Taken together, our results ascribe a novel function for USP37 in mitotic progression and further suggest that USP37 positively regulates the stability of chromatin-associated WAPL to facilitate sister chromatid resolution.
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors: Christina
authors: C
authors: Yeh
authors: Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors: Étienne
authors: É
authors: Coyaud
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
authors: Mikhail
authors: M
authors: Bashkurov
authors: Research Institute of Molecular Pathology (IMP), Dr. Bohr-Gasse 7, 1030 Vienna, Austria.
authors: Petra
authors: P
authors: van der Lelij
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
authors: Sally W T
authors: SW
authors: Cheung
authors: Research Institute of Molecular Pathology (IMP), Dr. Bohr-Gasse 7, 1030 Vienna, Austria.
authors: Jan Michael
authors: JM
authors: Peters
authors: Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors: Brian
authors: B
authors: Raught
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: pelletier@lunenfeld.ca.
authors: Laurence
authors: L
authors: Pelletier
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002842:Chromatids / Q000235:genetics* / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D020090:Chromosome Segregation; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D034622:RNA Interference; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D010450:Endopeptidases; D000097722:Cohesins; C559980:USP37 protein, human