Abstract
Defects in chromosome-microtubule attachment can cause chromosomal instability (CIN), frequently associated with infertility and aggressive cancers. Chromosome-microtubule attachment is mediated by a large macromolecular structure, the kinetochore. Sister kinetochores of each chromosome are pulled by microtubules from opposing spindle-poles, a state called biorientation which prevents chromosome missegregation. Kinetochore-microtubule attachments that lack the opposing-pull are detached by Aurora-B/Ipl1. It is unclear how mono-oriented attachments that precede biorientation are spared despite the lack of opposing-pull. Using an RNAi-screen, we uncover a unique role for the Astrin-SKAP complex in protecting mono-oriented attachments. We provide evidence of domains in the microtubule-end associated protein that sense changes specific to end-on kinetochore-microtubule attachments and assemble an outer-kinetochore crescent to stabilise attachments. We find that Astrin-PP1 and Cyclin-B-CDK1 pathways counteract each other to preserve mono-oriented attachments. Thus, CIN prevention pathways are not only surveying attachment defects but also actively recognising and stabilising mature attachments independent of biorientation.
Highlights
Defects in chromosome-microtubule attachment can cause chromosomal instability (CIN), frequently associated with infertility and aggressive cancers
Depletion of chTOG1, Astrin-SKAP complex, SKA complex, EB1-EB3 complex and CLIP170, all microtubule-associated proteins (MAPs), known to bind both the kinetochore and microtubule-ends, resulted in aberrant nuclei as expected, confirming chromosome missegregation induced by protein depletion (Supplementary Table 1)
Of the kinetochore associated MAPs known to deliver PP1, Astrin’s role is unique: Astrin-PP1 is recruited at end-on attached kinetochores (Fig. 7c), unlike CENP-E motor that binds to PP1 and delivers CLASP to naked unattached kinetochores[70]
Summary
Defects in chromosome-microtubule attachment can cause chromosomal instability (CIN), frequently associated with infertility and aggressive cancers. One potential way to protect a mono-oriented kinetochore-microtubule attachment from Aurora-B mediated error correction could be by establishing tension through its sister kinetochore’s interaction with microtubule walls, as lateral kinetochore-microtubule interactions are immune to centromeric Aurora-B27,28 This is unlikely to be the primary mechanism for at least two reasons: the outer-kinetochore region of human cells maintains active Aurora-B kinase (pT232)[27,29], which can destabilise lateral attachments[27]. The Astrin-SKAP/Kinastrin complex is recruited to endon, but not lateral, kinetochores during prometaphase[23] and is retained through metaphase and anaphase[41,42], while the SKA complex steadily increases in levels at the kinetochore during prometaphase and is retained during anaphase[43,44,45] Whether these phosphatase pools counteract distinct sets of kinases to control different stages of the chromosome-microtubule attachment process is not known
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