Regulation of sororin by Cdk1-mediated phosphorylation

Department of Biological Sciences, University of Toledo, 2801 W. Bancroft Street, MS 601, Toledo, OH 43606, USA.
Journal of Cell Science (Impact Factor: 5.43). 09/2011; 124(Pt 17):2976-87. DOI: 10.1242/jcs.085431
Source: PubMed


Tumor cells are commonly aneuploid, a condition contributing to cancer progression and drug resistance. Understanding how chromatids are linked and separated at the appropriate time will help uncover the basis of aneuploidy and will shed light on the behavior of tumor cells. Cohesion of sister chromatids is maintained by the multi-protein complex cohesin, consisting of Smc1, Smc3, Scc1 and Scc3. Sororin associates with the cohesin complex and regulates the segregation of sister chromatids. Sororin is phosphorylated in mitosis; however, the role of this modification is unclear. Here we show that mutation of potential cyclin-dependent kinase 1 (Cdk1) phosphorylation sites leaves sororin stranded on chromosomes and bound to cohesin throughout mitosis. Sororin can be precipitated from cell lysates with DNA-cellulose, and only the hypophosphorylated form of sororin shows this association. These results suggest that phosphorylation of sororin causes its release from chromatin in mitosis. Also, the hypophosphorylated form of sororin increases cohesion between sister chromatids, suggesting that phosphorylation of sororin by Cdk1 influences sister chromatid cohesion. Finally, phosphorylation-deficient sororin can alleviate the mitotic block that occurs upon knockdown of endogenous sororin. This mitotic block is abolished by ZM447439, an Aurora kinase inhibitor, suggesting that prematurely separated sister chromatids activate the spindle assembly checkpoint through an Aurora kinase-dependent pathway.

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Available from: Michael Bekier, Feb 26, 2014
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    • "The CPC acts in concert with Cdk1 to phosphorylate the cohesin-stabilizing protein Sororin (Dreier et al. 2011; Nishiyama et al. 2013). These phosphorylation events cause dissociation of Sororin from the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) leading to Wapl-mediated release of acetylated cohesin from chromosome arms and loss of cohesion (Dreier et al. 2011; Kueng et al. 2006; Nishiyama et al. 2013). In addition, the CPC may enhance chromosome compaction by loading of Condensin I onto chromosomal arms (Lipp et al. 2007; Takemoto et al. 2007). "
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    • "Additionally, as the aurora kinase inhibitor ZM 447439 (#46) reduced TDP-43 stress granule formation without effect on HuR-positive stress granules, we examined additional aurora kinase inhibitors 4-(4′-benzamidoanilino)-6,7-dimethoxyquinazoline and cyclopropanecarboxylic acid-(3-(4-(3-trifluoromethyl-phenylamino)-pyrimidin-2-ylamino)-phenyl)-amide, however, neither reduced TDP-43-positive stress granule formation. Aurora kinases are often associated with the same cellular processes as CDKs [41], therefore, it is possible that its effect on TDP-43-positive stress granules is also via a similar mechanism (Table S3). Similarly, four of five inhibitors against MEK reduced both TDP-43 and HuR-positive stress granule formation (Table S3). "
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