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Cell. 2014 Feb 27;156(5):1017-31. doi: 10.1016/j.cell.2014.01.010.

Nuclear pores protect genome integrity by assembling a premitotic and Mad1-dependent anaphase inhibitor.

Author information

1
Molecular Biology Program and Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Swiss Federal Institute of Technology Zürich, CH-8093 Zürich, Switzerland; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
3
The Gurdon Institute and Department of Zoology, University of Cambridge, Cambridge CB2 1QN, UK.
4
Center for Frontier Research, National Institute of Genetics, ROIS, and Department of Genetics, SOKENDAI, Yata 1111, Mishima, Shizuoka 411-8540, Japan.
5
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
6
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.

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.

PMID:
24581499
PMCID:
PMC3947552
DOI:
10.1016/j.cell.2014.01.010
[Indexed for MEDLINE]
Free PMC Article

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