title: Nuclear pores protect genome integrity by assembling a premitotic and Mad1-dependent anaphase inhibitor.
abstract: The spindle assembly checkpoint (SAC) delays anaphase until all chromosomes are bioriented on the mitotic spindle. Under current models, unattached kinetochores transduce the SAC by catalyzing the intramitotic production of a diffusible inhibitor of APC/C(Cdc20) (the anaphase-promoting complex/cyclosome and its coactivator Cdc20, a large ubiquitin ligase). Here we show that nuclear pore complexes (NPCs) in interphase cells also function as scaffolds for anaphase-inhibitory signaling. This role is mediated by Mad1-Mad2 complexes tethered to the nuclear basket, which activate soluble Mad2 as a binding partner and inhibitor of Cdc20 in the cytoplasm. Displacing Mad1-Mad2 from nuclear pores accelerated anaphase onset, prevented effective correction of merotelic errors, and increased the threshold of kinetochore-dependent signaling needed to halt mitosis in response to spindle poisons. A heterologous Mad1-NPC tether restored Cdc20 inhibitor production and normal M phase control. We conclude that nuclear pores and kinetochores both emit "wait anaphase" signals that preserve genome integrity.
authors.affiliation: Molecular Biology Program and Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Rodriguez-Bravo
authors.affiliation: Molecular Biology Program and Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: John
authors.initials: J
authors.lastname: Maciejowski
authors.affiliation: Molecular Biology Program and Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Corona
authors.affiliation: Swiss Federal Institute of Technology Zürich, CH-8093 Zürich, Switzerland; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Håkon Kirkeby
authors.initials: HK
authors.lastname: Buch
authors.affiliation: The Gurdon Institute and Department of Zoology, University of Cambridge, Cambridge CB2 1QN, UK.
authors.forename: Philippe
authors.initials: P
authors.lastname: Collin
authors.affiliation: Center for Frontier Research, National Institute of Genetics, ROIS, and Department of Genetics, SOKENDAI, Yata 1111, Mishima, Shizuoka 411-8540, Japan.
authors.forename: Masato T
authors.initials: MT
authors.lastname: Kanemaki
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jagesh V
authors.initials: JV
authors.lastname: Shah
authors.affiliation: Molecular Biology Program and Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: jallepap@mskcc.org.
authors.forename: Prasad V
authors.initials: PV
authors.lastname: Jallepalli
mesh_terms: D021581:Active Transport, Cell Nucleus; D000705:Anaphase; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D007399:Interphase; D018386:Kinetochores / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints; D064246:Mad2 Proteins / Q000378:metabolism*; D008938:Mitosis; D022022:Nuclear Pore / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C501384:MAD1L1 protein, human; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D009687:Nuclear Proteins