1. Division of Molecular Medicine, Wadsworth Center, Albany, New York State Department of Health, Albany, New York 12201-0509, USA
2. Department of Biomedical Sciences, State University of New York, Albany, New York 12222, USA
3. Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, New York 10021, USA
4. These authors contributed equally to this work.
5. Present address: Department of Cytology, Biology Faculty, Moscow State University, Moscow 119991, Russia.

Correspondence to: Tarun M. Kapoor³Alexey Khodjakov^1,2,3 Correspondence and requests for materials should be addressed to A.K. (Email: khodj@wadsworth.org) or T.M.K. (Email: kapoor@rockefeller.edu).

Abstract

Accurate segregation of chromosomes, essential for the stability of the genome, depends on 'bi-orientation'—simultaneous attachment of each individual chromosome to both poles of the mitotic spindle¹. On bi-oriented chromosomes, kinetochores (macromolecular complexes that attach the chromosome to the spindle) reside on the opposite sides of the chromosome's centromere². In contrast, sister kinetochores shift towards one side of the centromere on 'syntelic' chromosomes that erroneously attach to one spindle pole with both sister kinetochores. Syntelic attachments often arise during spindle assembly and must be corrected to prevent chromosome loss³. It is assumed that restoration of proper centromere architecture occurs automatically owing to elastic properties of the centromere^{1, 2}. Here we test this assumption by combining laser microsurgery and chemical biology assays in cultured mammalian cells. We find that kinetochores of syntelic chromosomes remain juxtaposed on detachment from spindle microtubules. These findings reveal that correction of syntelic attachments involves an extra step that has previously been overlooked: external forces must be applied to move sister kinetochores to the opposite sides of the centromere. Furthermore, we demonstrate that the shape of the centromere is important for spindle assembly, because bipolar spindles do not form in cells lacking centrosomes when multiple chromosomes with juxtaposed kinetochores are present. Thus, proper architecture of the centromere makes an important contribution to achieving high fidelity of chromosome segregation.

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