Quantifying Changes in Chromosome Position to Assess Chromokinesin Activity

Thompson, Alex F.; Vandal, Sarah E.; Stumpff, Jason

doi:10.1007/978-1-0716-1904-9_10

Cited by 2 publications

(2 citation statements)

References 20 publications

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“…A circular ROI with a 12.5 μm radius was centered around the spindle pole of each cell, and the radial profile of DAPI signal intensity at distances from the pole was measured (Radial Profile Plot plugin; https://imagej.nih.gov/ij/plugins/radial-profile.html ). The distance from the pole to the maximum DAPI signal was calculated for each cell as a measure of relative polar ejection forces ( Thompson et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation

Thompson

Blackburn

Arons

et al. 2022

eLife

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The chromokinesin KIF22 generates forces that contribute to mitotic chromosome congression and alignment. Mutations in the a2 helix of the motor domain of KIF22 have been identified in patients with abnormal skeletal development, and we report the identification of a patient with a novel mutation in the KIF22 tail. We demonstrate that pathogenic mutations do not result in a loss of KIF22's functions in early mitosis. Instead, mutations disrupt chromosome segregation in anaphase, resulting in reduced proliferation, abnormal daughter cell nuclear morphology, and, in a subset of cells, cytokinesis failure. This phenotype could be explained by a failure of KIF22 to inactivate in anaphase. Consistent with this model, constitutive activation of the motor via a known site of phosphoregulation in the tail phenocopied the effects of pathogenic mutations. These results suggest the motor domain a2 helix may be an important site for regulation of KIF22 activity at the metaphase to anaphase transition. In support of this conclusion, mimicking phosphorylation of a2 helix residue T158 also prevents inactivation of KIF22 in anaphase. These findings demonstrate the importance of both the head and tail of the motor in regulating the activity of KIF22 and offer insight into the cellular consequences of preventing KIF22 inactivation and disrupting force balance in anaphase.

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Section: Methodsmentioning

confidence: 99%

Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation

Thompson

Blackburn

Arons

et al. 2022

eLife

Self Cite

View full text Add to dashboard Cite

show abstract

“…A circular ROI with a 12.5 μm radius was centered around the spindle pole of each cell, and the radial profile of DAPI signal intensity at distances from the pole was measured (Radial Profile Plot plugin, https://imagej.nih.gov/ij/plugins/radial-profile.html). The distance from the pole to the maximum DAPI signal was calculated for each cell as a measure of relative polar ejection forces (Thompson, Vandal, & Stumpff, 2022).…”

Section: Methodsmentioning

confidence: 99%

Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation

Thompson

Blackburn

Babovic‐Vuksanovic

et al. 2021

Preprint

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The chromokinesin KIF22 uses plus end-directed motility and direct binding to chromosome arms to generate pushing forces that contribute to mitotic chromosome congression and alignment. Mutations in the motor domain of KIF22 have been identified in patients with abnormal skeletal development, and we report the identification of a patient with a novel mutation in the coiled-coil domain of the KIF22 tail. The mechanism by which these mutations affect development is unknown. We assessed whether pathogenic mutations affect the function of KIF22 in mitosis and demonstrate that mutations do not result in a loss of KIF22 function. Pathogenic mutations did not alter the localization or prometaphase function of KIF22. Instead, mutations disrupted chromosome segregation in anaphase, resulting in reduced proliferation, abnormal daughter cell nuclear morphology and, in a subset of cells, cytokinesis failure. This phenotype could be explained by a failure of KIF22 to inactivate in anaphase. Consistent with this model, a phosphomimetic mutation, which constitutively activates the motor, phenocopied the effects of pathogenic mutations. These findings offer insight into the mechanism by which mutations in KIF22 may affect human development, the balance between polar ejection forces and antiparallel microtubule sliding in anaphase, and potential mechanisms of KIF22 regulation.

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Quantifying Changes in Chromosome Position to Assess Chromokinesin Activity

Cited by 2 publications

References 20 publications

Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation

Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation

Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation

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