Rapid effects of acute anoxia on spindle kinetochore interactions activate the mitotic spindle checkpoint.
The dramatic chromosome instability in certain tumors might reflect a synergy of spindle checkpoint defects with hypoxic conditions. In Caenorhabditis elegans and Drosophila melanogaster, spindle checkpoint activation has been implicated in the response to acute anoxia. The activation mechanism is unknown. Our analyses in D. melanogaster demonstrate that oxygen deprivation affects microtubule organization within minutes. The rapid effects of anoxia are identical in wild-type and spindle checkpoint-deficient Mps1 mutant embryos. Therefore, the anoxia effects on the mitotic spindle are not a secondary consequence of spindle checkpoint activation. Some motor, centrosome and kinetochore proteins (dynein, Kin-8, Cnn, TACC, Cenp-C, Nuf2) are rapidly relocalized after oxygen deprivation. Kinetochores congress inefficiently into the metaphase plate and do not experience normal pulling forces. Spindle checkpoint proteins accumulate mainly within the spindle midzone and inhibit anaphase onset. In checkpoint-deficient embryos, mitosis is still completed after oxygen deprivation, although accompanied by massive chromosome missegregation. Inhibitors of oxidative phosphorylation mimic anoxia effects. We conclude that oxygen deprivation impairs the chromosome segregation machinery more rapidly than spindle checkpoint function. Although involving adenosine triphosphate (ATP)-consuming kinases, the spindle checkpoint can therefore be activated by spindle damage in response to acute anoxia and protect against aneuploidies.
Pandey
Rahul
R
Department of Genetics, BZMB, University of Bayreuth, 95440 Bayreuth, Germany.
Heeger
Sebastian
S
Lehner
Christian F
CF
D000693:Anaerobiosis / Q000187:drug effects; D000818:Animals; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018386:Kinetochores / Q000187:drug effects / Q000378:metabolism*; D020409:Molecular Motor Proteins / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism*
D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D020409:Molecular Motor Proteins; D003576:Electron Transport Complex IV; D010100:Oxygen