Deficiency in SNM1 abolishes an early mitotic checkpoint induced by spindle stress.
Spindle poisons represent an important class of anticancer drugs that act by interfering with microtubule polymerization and dynamics and thereby induce mitotic checkpoints and apoptosis. Here we show that mammalian SNM1 functions in an early mitotic stress checkpoint that is distinct from the well-characterized spindle checkpoint that regulates the metaphase-to-anaphase transition. Specifically, we found that compared to wild-type cells, Snm1-deficient mouse embryonic fibroblasts exposed to spindle poisons exhibited elevated levels of micronucleus formation, decreased mitotic delay, a failure to arrest in mitosis prior to chromosome condensation, supernumerary centrosomes, and decreased viability. In addition, we show that both Snm1 and 53BP1, previously shown to interact, coimmunoprecipitate with components of the anaphase-promoting complex (APC)/cyclosome. These findings suggest that Snm1 is a component of a mitotic stress checkpoint that negatively targets the APC prior to chromosome condensation.
Akhter
Shamima
S
University of Texas M. D. Anderson Cancer Center, Department of Molecular Genetics, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Richie
Christopher T
CT
Deng
Jian Min
JM
Brey
Eric
E
Zhang
Xiaoshan
X
Patrick
Charles
C
Behringer
Richard R
RR
Legerski
Randy J
RJ
D000705:Anaphase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002875:Chromosomes / Q000648:ultrastructure; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D004706:Endodeoxyribonucleases; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008677:Metaphase; D051379:Mice; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis; D009154:Mutation; D015739:Nocodazole / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000502:physiology*; D008941:Spindle Apparatus; D013312:Stress, Physiological; D013997:Time Factors; D000071857:Tumor Suppressor p53-Binding Protein 1
D000970:Antineoplastic Agents; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C092537:Ifi202b protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D029701:Saccharomyces cerevisiae Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D042846:CDC2-CDC28 Kinases; D004706:Endodeoxyribonucleases; C090162:PSO2 protein, S cerevisiae; D015739:Nocodazole