Abstract
Aneuploidy – chromosome instability leading to incorrect chromosome number in dividing cells – can arise from defects in centrosome duplication, bipolar spindle formation, kinetochore-microtubule attachment, chromatid cohesion, mitotic checkpoint monitoring, or cytokinesis. As most tumors show some degree of aneuploidy, mechanistic understanding of these pathways has been an intense area of research to provide potential therapeutics. Here, we present a mechanism for aneuploidy in fission yeast based on spindle pole microtubule defocusing by loss of kinesin-14 Pkl1, leading to kinesin-5 Cut7-dependent aberrant long spindle microtubule minus end protrusions that push the properly segregated chromosomes to the site of cell division, resulting in chromosome cut at cytokinesis. Pkl1 localization and function at the spindle pole is mutually dependent on spindle pole-associated protein Msd1. This mechanism of aneuploidy bypasses the known spindle assembly checkpoint that monitors chromosome segregation.
Highlights
Aneuploidy—chromosome instability leading to incorrect chromosome number in dividing cells—can arise from defects in centrosome duplication, bipolar spindle formation, kinetochore–microtubule attachment, chromatid cohesion, mitotic checkpoint monitoring or cytokinesis
Kinesin-14, which includes human HSET, Xenopus XCTK2, Drosophila NCD, Saccharomyces cerevisiae Kar[3] and Schizosaccharomyces pombe Pkl[1], is an MT minus-end-directed motor localized to the spindle poles, which are able to cross-link parallel MTs to focus the spindle pole during mitosis and meiosis, and are able to antagonize kinesin-5, an MT plus end-directed motor localized at the spindle midzone, in a force–balance equilibrium to maintain proper spindle length architecture and function[6,7]
We show in fission yeast that loss of kinesin-14 Pkl[1] leads to aberrant spindle pole MT protrusions, resulting from kinesin-5 Cut[7] sliding the unfocused pole MTs
Summary
Aneuploidy—chromosome instability leading to incorrect chromosome number in dividing cells—can arise from defects in centrosome duplication, bipolar spindle formation, kinetochore–microtubule attachment, chromatid cohesion, mitotic checkpoint monitoring or cytokinesis. We present a mechanism for aneuploidy in fission yeast based on spindle pole microtubule defocusing by loss of kinesin-14 Pkl[1], leading to kinesin-5 Cut7-dependent aberrant long spindle microtubule minus-end protrusions that push the properly segregated chromosomes to the site of cell division, resulting in chromosome cut at cytokinesis. We show in fission yeast that loss of kinesin-14 Pkl[1] leads to aberrant spindle pole MT protrusions, resulting from kinesin-5 Cut[7] sliding the unfocused pole MTs. Long MT protrusions can subsequently push the post anaphase segregated chromosomes to the site of cell division, resulting in chromosome cut at cytokinesis, producing aneuploid cells. Fission yeast S. pombe Pkl[1] acts to the metazoan kinesin-14 It is a diffusive MT minus-end-directed motor[14], localizing at the spindle pole body (SPB) during mitosis[15,16,17]. Short MT protrusions showed Mal3-GFP at their ends, extended at rate of Vextension 1⁄4 1.7 mm min À 1, persisted growing for Tcatastrophe 1⁄4 0.8 min, exhibited mC-Atb[2] Cut11-GFP mC-Atb[2] Sid4-GFP wt 0 Metaphase 4 8 12 Anaphase 16 20 24 28 min pkl[1] wt 0 Anaphase 2 4 6 8 10 12 14 min pkl[1]
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