title: APC2 and Axin promote mitotic fidelity by facilitating centrosome separation and cytoskeletal regulation.
abstract: To ensure the accurate transmission of genetic material, chromosome segregation must occur with extremely high fidelity. Segregation errors lead to chromosomal instability (CIN), with deleterious consequences. Mutations in the tumor suppressor adenomatous polyposis coli (APC) initiate most colon cancers and have also been suggested to promote disease progression through increased CIN, but the mechanistic role of APC in preventing CIN remains controversial. Using fly embryos as a model, we investigated the role of APC proteins in CIN. Our findings suggest that APC2 loss leads to increased rates of chromosome segregation error. This occurs through a cascade of events beginning with incomplete centrosome separation leading to failure to inhibit formation of ectopic cleavage furrows, which result in mitotic defects and DNA damage. We test several hypotheses related to the mechanism of action of APC2, revealing that APC2 functions at the embryonic cortex with several protein partners, including Axin, to promote mitotic fidelity. Our in vivo data demonstrate that APC2 protects genome stability by modulating mitotic fidelity through regulation of the cytoskeleton.
authors.affiliation: Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Poulton
authors.forename: Frank W
authors.initials: FW
authors.lastname: Mu
authors.forename: David M
authors.initials: DM
authors.lastname: Roberts
authors.forename: Mark
authors.initials: M
authors.lastname: Peifer
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D060466:Axin Protein / Q000378:metabolism*; D018385:Centrosome / Q000378:metabolism; D043171:Chromosomal Instability; D020090:Chromosome Segregation; D003599:Cytoskeleton / Q000378:metabolism; D004249:DNA Damage; D004330:Drosophila / Q000196:embryology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C467323:APC2 protein, Drosophila; D060466:Axin Protein; C118000:Axn protein, Drosophila; D029721:Drosophila Proteins; D025521:Tumor Suppressor Proteins
keywords: APC; Axin; Chromosome segregation; Cytoskeleton; Drosophila; Genome stability
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