TY - JOUR
T1 - Nuclear pores protect genome integrity by assembling a premitotic and mad1-dependent anaphase inhibitor
AU - Rodriguez-Bravo, Veronica
AU - Maciejowski, John
AU - Corona, Jennifer
AU - Buch, Håkon Kirkeby
AU - Collin, Philippe
AU - Kanemaki, Masato T.
AU - Shah, Jagesh V.
AU - Jallepalli, Prasad V.
N1 - Funding Information:
We thank N. Gray, J. Hanover, A. Musacchio, and E. Nigg for generous gifts of reagents, M. Leversha (MSKCC Cytogenetics Core) for performing FISH, and A. North (Bio-Imaging Resource Center, Rockefeller University) and K. Manova (MSKCC Molecular Cytology Core) for help with confocal imaging. We are grateful to F. Cubizolles for help in preparing the Venus-Mad2 targeting construct and E. Foley for assistance with live-cell imaging. P.C. was funded via a BBSRC project grant. This work was supported by NIH grants R01GM077238 to J.V.S. and R01GM094972 to P.V.J.
PY - 2014/2/27
Y1 - 2014/2/27
N2 - 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/CCdc20 (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.
AB - 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/CCdc20 (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.
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U2 - 10.1016/j.cell.2014.01.010
DO - 10.1016/j.cell.2014.01.010
M3 - Article
C2 - 24581499
AN - SCOPUS:84896859109
SN - 0092-8674
VL - 156
SP - 1017
EP - 1031
JO - Cell
JF - Cell
IS - 5
ER -