A Last-Minute Rescue of Trapped Chromatin
ABSTRACT Chromosome segregation and cytokinesis must be tightly coordinated to ensure that chromosomes are accurately partitioned between dividing cells. In this issue, Steigemann et al. (2009) report that Aurora B kinase promotes proper chromosome segregation by delaying abscission when chromatin is trapped between dividing cells.
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ABSTRACT: Eukaryotic cell division is an orderly and timely process involving the error-free segregation of chromosomes and cytoplasmic components to give rise to two separate daughter cells. Defects in genome maintenance mechanisms such as cell cycle checkpoints and DNA repair can impact the segregation of the genome during mitosis leading to multiple chromosomal imbalances. In mammals, the DNA damage checkpoint effector Checkpoint Kinase 1 (Chk1) is essential for responses to DNA replication errors, external DNA damage, and chromatin breaks. We reported recently that Chk1 also was essential for chromosome segregation and completion of cytokinesis to prevent genomic instability. Our studies demonstrated that Chk1 deficiency in mitotic cells causes chromosome mis-alignment, lagging chromosomes, chromosome mis-segregation, cytokinetic regression and binucleation. In addition, abrogation of Chk1 resulted in aberrant localization of mitotic Aurora B kinase at the metaphase plate, anaphase spindle midzone, and cytokinetic midbody as studied both in various cell lines and in a mouse model. Therefore, inappropriate regulation of Chk1 levels during cell cycle progression will result in failed cell division and enhanced genomic instability.Cell cycle (Georgetown, Tex.) 09/2009; 8(15):2339-42. DOI:10.4161/cc.8.15.9169 · 5.01 Impact Factor
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ABSTRACT: Aurora B is critically involved in ensuring proper cytokinesis and maintaining genomic stability. The tumor suppressor RASSF1A regulates cell cycle progression by regulating mitotic progression, G(1)-S transition, and microtubule stability. We previously reported that both Aurora A and Aurora B phosphorylate RASSF1A, and showed that phosphorylation of RASSF1A by Aurora A blocks the inhibitory function of RASSF1A toward anaphase-promoting complex-Cdc20. However, the role of Aurora B-mediated RASSF1A phosphorylation remains unknown. Here, we show that phosphorylation of RASSF1A on Ser203 by Aurora B during late mitosis has a critical role in regulating cytokinesis. Notably, RASSF1A interacts with Syntaxin16, a member of the t-SNARE family, at the midzone and midbody during late mitosis. Aurora B is required for this interaction and for the subsequent recruitment of Syntaxin16 to the midzone and midbody, a prerequisite for the successful completion of cytokinesis. Furthermore, Aurora B depletion results in a failure of Syntaxin16 to properly localize to the midzone and midbody, a mislocalization that was prevented by overexpression of the phosphomimetic RASSF1A (S203D) mutant. Finally, either depletion of Syntaxin16 or expression of the nonphosphorylatable RASSF1A (S203A) mutant results in cytokinesis defects. Our findings implicate Aurora B-mediated phosphorylation of RASSF1A in the regulation of cytokinesis.Cancer Research 11/2009; 69(22):8540-4. DOI:10.1158/0008-5472.CAN-09-1554 · 9.28 Impact Factor
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ABSTRACT: Correct assembly of nuclear pore complexes (NPCs), which directly and indirectly control nuclear environment and architecture, is vital to genomic regulation. We previously found that nucleoporin 153 (Nup 153) is required for timely progression through late mitosis. In this study, we report that disruption of Nup 153 function by either small interfering RNA-mediated depletion or expression of a dominant-interfering Nup 153 fragment results in dramatic mistargeting of the pore basket components Tpr and Nup 50 in midbody-stage cells. We find a concomitant appearance of aberrantly localized active Aurora B and an Aurora B-dependent delay in abscission. Depletion of Nup 50 is also sufficient to increase the number of midbody-stage cells and, likewise, triggers distinctive mislocalization of Aurora B. Together, our results suggest that defects in nuclear pore assembly, and specifically the basket structure, at this time of the cell cycle activate an Aurora B-mediated abscission checkpoint, thereby ensuring that daughter cells are generated only when fully formed NPCs are present.The Journal of Cell Biology 11/2010; 191(5):923-31. DOI:10.1083/jcb.201007124 · 9.69 Impact Factor