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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Anaphase*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Dimerization
  • HCT116 Cells
  • HeLa Cells
  • Humans
  • Interphase
  • Kinetochores / metabolism
  • M Phase Cell Cycle Checkpoints*
  • Mad2 Proteins / metabolism*
  • Mitosis
  • Nuclear Pore / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*


  • Cell Cycle Proteins
  • MAD1L1 protein, human
  • MAD2L1 protein, human
  • Mad2 Proteins
  • Nuclear Proteins