Spatial and temporal control of mitotic chromosome movements.

有丝分裂染色体运动的空间和时间控制。

• 批准号: 10201645
• 负责人: JASON K STUMPFF
• 金额: $ 30.57万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-05 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201645
• 关键词: Address; Affect; Affinity; Binding; Biochemical; Biological Assay; Biophysics; Biosensor; C-terminal; Cell division; Cells; Chromosomes; Complex; Coupled; Defect; Development; Equilibrium; Event; Exhibits; Fluorescence Resonance Energy Transfer; Genomic Instability; Germ Cells; Goals; Growth; In Vitro; Infertility; Kinesin; Kinetochores; Lysine; Mammalian Cell; Measures; Metaphase; Microtubule-Associated Proteins; Microtubules; Mitosis; Mitotic; Mitotic Chromosome; Mitotic spindle; Modeling; Molecular; Motor; Movement; Mutagenesis; Neck; Phenotype; Phosphorylation; Play; Plus End of the Microtubule; Process; Prometaphase; Protein Dephosphorylation; Protein phosphatase; Proteins; Public Health; Regulation; Research; Role; Signal Transduction; Site; Structure; Syndrome; Testing; Time; Translating; Trisomy; United States; Variant; Work; attenuation; aurora B kinase; aurora kinase; base; biophysical properties; cell motility; chromosome movement; genome integrity; innovation; live cell imaging; neoplastic cell; novel; prevent; recruit; single molecule; treadmill; tumor

PROJECT SUMMARY The alignment of chromosomes during metaphase is one of the most well conserved events in cell division, yet the molecular mechanisms that underlie this process are not understood. As cells progress from prometaphase into metaphase, chromosomes are aligned at the equator of the mitotic spindle through (A) the spatial restriction of their movements and (B) an increase in attachments between kinetochores and microtubules. The mechanisms that temporally coordinate the confinement of chromosome movements with increased attachments have not been identified. The kinesin-like motor Kif18A (kinesin-8) is required for the alignment of all chromosomes in mitotic cells, however, the motor's role in this process is not fully understood. During mitosis, Kif18A concentrates at the plus-ends of kinetochore-microtubules, which generate the primary forces that move chromosomes. The proposed studies will address key questions related to understanding how Kif18A functions mechanistically during chromosome alignment including: (A) how does Kif18A access the plus-ends of kinetochore-microtubules, which are embedded in a dense protein matrix, (B) how do Kif18A ensembles affect kinetochore-microtubule-generated forces, and (C) how does Kif18A increase attachments between kinetochores and microtubules. The primary goal of the proposed work is to answer these questions by determining how Kif18A's biochemical and biophysical properties translate to its complex effects on the movements and attachments of mitotic chromosomes. We hypothesize that the accumulation of Kif18A at kinetochore-microtubule plus-ends temporally coordinates the spatial confinement of chromosome movements with increased kinetochore-microtubule attachments through two independent mechanisms. We will use an approach combining single molecule biophysics, quantitative live cell imaging, and structural mutagenesis to test these predictions.

项目总结 中期染色体的排列是细胞分裂中最保守的事件之一， 然而，这一过程背后的分子机制尚不清楚。随着细胞从 前中期到中期，染色体通过(A)在有丝分裂纺锤体的赤道上排列。 他们行动的空间限制以及(B)运动中枢和运动中枢之间依恋的增加 微管。在时间上协调限制染色体运动的机制与 更多的依恋还没有确定。需要激动素样电机Kif18A(激动素-8) 有丝分裂细胞中所有染色体的排列，然而，马达在这一过程中的作用并不完全 明白了。在有丝分裂期间，Kif18A集中在动粒微管的正端，这 产生推动染色体运动的原始力。拟议的研究将解决关键问题 与了解Kif18A在染色体比对过程中的机械作用有关，包括：(A) Kif18A是如何获得动粒微管的加端的，这些微管嵌入在致密的 蛋白质基质，(B)Kif18A集合如何影响动粒-微管生成的力，以及(C)如何 Kif18A是否增加了动点和微管之间的附着性？的主要目标是 拟议的工作是通过确定Kif18A的生化和生物物理如何 特性转化为其对有丝分裂染色体的运动和附着的复杂影响。我们 假设Kif18A在动粒-微管+末端的积累是时间坐标 着丝粒-微管附着性增加对染色体运动的空间限制 通过两个独立的机制。我们将使用一种结合单分子生物物理学的方法， 定量活细胞成像和结构突变来测试这些预测。

项目成果

Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition.

• DOI: 10.1038/s41586-020-03114-6
• 发表时间: 2021-03
• 期刊: Nature
• 影响因子: 64.8
• 作者: Cohen-Sharir Y;McFarland JM;Abdusamad M;Marquis C;Bernhard SV;Kazachkova M;Tang H;Ippolito MR;Laue K;Zerbib J;Malaby HLH;Jones A;Stautmeister LM;Bockaj I;Wardenaar R;Lyons N;Nagaraja A;Bass AJ;Spierings DCJ;Foijer F;Beroukhim R;Santaguida S;Golub TR;Stumpff J;Storchová Z;Ben-David U
• 通讯作者: Ben-David U

Kinesin-binding protein remodels the kinesin motor to prevent microtubule binding.

• DOI: 10.1126/sciadv.abj9812
• 发表时间: 2021-11-19
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Solon AL;Tan Z;Schutt KL;Jepsen L;Haynes SE;Nesvizhskii AI;Sept D;Stumpff J;Ohi R;Cianfrocco MA
• 通讯作者: Cianfrocco MA

Chromosomally unstable tumor cells specifically require KIF18A for proliferation.

• DOI: 10.1038/s41467-021-21447-2
• 发表时间: 2021-02-22
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Marquis C;Fonseca CL;Queen KA;Wood L;Vandal SE;Malaby HLH;Clayton JE;Stumpff J
• 通讯作者: Stumpff J

Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation.

• DOI: 10.7554/elife.78653
• 发表时间: 2022-06-22
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Thompson, Alex F.;Blackburn, Patrick R.;Arons, Noah S.;Stevens, Sarah N.;Babovic-Vuksanovic, Dusica;Lian, Jane B.;Klee, Eric W.;Stumpff, Jason
• 通讯作者: Stumpff, Jason

Mitotically-Associated lncRNA (MANCR) Affects Genomic Stability and Cell Division in Aggressive Breast Cancer.

• DOI: 10.1158/1541-7786.mcr-17-0548
• 发表时间: 2018-04
• 期刊: Molecular cancer research : MCR
• 作者: Tracy KM;Tye CE;Ghule PN;Malaby HLH;Stumpff J;Stein JL;Stein GS;Lian JB
• 通讯作者: Lian JB