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Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation

The chromokinesin KIF22 generates forces that contribute to mitotic chromosome congression and alignment. Mutations in the α2 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...

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Autores principales: Thompson, Alex F, Blackburn, Patrick R, Arons, Noah S, Stevens, Sarah N, Babovic-Vuksanovic, Dusica, Lian, Jane B, Klee, Eric W, Stumpff, Jason
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9302971/
https://www.ncbi.nlm.nih.gov/pubmed/35730929
http://dx.doi.org/10.7554/eLife.78653
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author Thompson, Alex F
Blackburn, Patrick R
Arons, Noah S
Stevens, Sarah N
Babovic-Vuksanovic, Dusica
Lian, Jane B
Klee, Eric W
Stumpff, Jason
author_facet Thompson, Alex F
Blackburn, Patrick R
Arons, Noah S
Stevens, Sarah N
Babovic-Vuksanovic, Dusica
Lian, Jane B
Klee, Eric W
Stumpff, Jason
author_sort Thompson, Alex F
collection PubMed
description The chromokinesin KIF22 generates forces that contribute to mitotic chromosome congression and alignment. Mutations in the α2 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 that the motor domain α2 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 α2 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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spelling pubmed-93029712022-07-22 Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation Thompson, Alex F Blackburn, Patrick R Arons, Noah S Stevens, Sarah N Babovic-Vuksanovic, Dusica Lian, Jane B Klee, Eric W Stumpff, Jason eLife Cell Biology The chromokinesin KIF22 generates forces that contribute to mitotic chromosome congression and alignment. Mutations in the α2 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 that the motor domain α2 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 α2 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. eLife Sciences Publications, Ltd 2022-06-22 /pmc/articles/PMC9302971/ /pubmed/35730929 http://dx.doi.org/10.7554/eLife.78653 Text en © 2022, Thompson et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Thompson, Alex F
Blackburn, Patrick R
Arons, Noah S
Stevens, Sarah N
Babovic-Vuksanovic, Dusica
Lian, Jane B
Klee, Eric W
Stumpff, Jason
Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation
title Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation
title_full Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation
title_fullStr Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation
title_full_unstemmed Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation
title_short Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation
title_sort pathogenic mutations in the chromokinesin kif22 disrupt anaphase chromosome segregation
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9302971/
https://www.ncbi.nlm.nih.gov/pubmed/35730929
http://dx.doi.org/10.7554/eLife.78653
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