A5009814990- Microtubule and mitosis dynamics
- Genomics and Chromatin Dynamics
- Cancer Genomics and Diagnostics
- Cancer-related molecular mechanisms research
- Epigenetics and DNA Methylation
- DNA Repair Mechanisms
- Cellular Mechanics and Interactions
- Cellular transport and secretion
- Photosynthetic Processes and Mechanisms
- Ubiquitin and proteasome pathways
- Molecular Biology Techniques and Applications
- Chromosomal and Genetic Variations
- Protist diversity and phylogeny
- RNA modifications and cancer
- Pluripotent Stem Cells Research
- Nuclear Structure and Function
- MicroRNA in disease regulation
- Micro and Nano Robotics
- RNA Research and Splicing
- Cancer-related Molecular Pathways
- Hippo pathway signaling and YAP/TAZ
- BRCA gene mutations in cancer
- Glioma Diagnosis and Treatment
- Glycosylation and Glycoproteins Research
- Erythrocyte Function and Pathophysiology
University of Vermont
2016-2025
John Wiley & Sons (United States)
2015
Hudson Institute
2015
University of California, Los Angeles
2015
Institute for Molecular Medicine
2015
University of Washington
2007-2012
University of Colorado Boulder
2000-2009
Metaphase chromosome positioning depends on Kif18A, a kinesin-8 that accumulates at and suppresses the dynamics of K-MT plus ends. By engineering Kif18A mutants suppress MT but fail to concentrate ends, we identify mechanism allows accumulate ends level required movements. Enrichment its C-terminal tail domain, while ability growth is conferred by N-terminal motor domain. The contains second MT-binding domain diffuses along lattice, suggesting it tethers track. Consistently, enhances...
Chromosomal instability (CIN) is a hallmark of tumor cells caused by changes in the dynamics and control microtubules that compromise mitotic spindle. Thus, CIN may respond differently than diploid to treatments target spindle regulation. Here, we test this idea inhibiting subset kinesin motor proteins involved control. KIF18A required for proliferation derived from triple negative breast cancer or colorectal tumors but not near-diploid cells. Following inhibition, exhibit delays, multipolar...
Chromosome alignment at the equator of mitotic spindle is a highly conserved step during cell division; however, its importance to genomic stability and cellular fitness not understood. Normal mammalian somatic cells lacking KIF18A function complete division without aligning chromosomes. These alignment-deficient display normal chromosome copy numbers in vitro vivo, suggesting that largely dispensable for maintenance euploidy. However, we find loss leads interchromosomal compaction defects...
Chromosome instability is a prevalent vulnerability of cancer cells that has yet to be fully exploited therapeutically. To identify genes uniquely essential chromosomally unstable cells, we mined the Cancer Dependency Map for in tumor with high levels copy number aberrations. We and validate KIF18A, mitotic kinesin, as cells. Knockdown KIF18A leads defects reduction growth. Screening chemical library inhibitors enzymatic activity identified hit was optimized yield VLS-1272, which orally...
Abstract Aggressive breast cancer is difficult to treat as it unresponsive many hormone-based therapies; therefore, imperative identify novel, targetable regulators of progression. Long non-coding RNAs (lncRNA) are important in and have great potential therapeutic targets; however, little known about how the majority lncRNAs function within cancer. This study characterizes a novel lncRNA, MANCR (mitotically-associated long noncoding RNA; LINC00704), which upregulated patient specimens cells....
Oxidative damage to telomere DNA compromises integrity. We recently reported that the glycosylase NEIL3 preferentially repairs oxidative lesions in sequences vitro. Here, we show loss of causes anaphase bridging because dysfunction. expression increases during S phase and reaches maximal levels late S/G2. co-localizes with TRF2 associates telomeres phase, this association upon stress. Mechanistic studies reveal binds single-stranded via its intrinsically disordered C terminus a...
Kinesin-5 motors organize mitotic spindles by sliding apart microtubules. They are homotetramers with dimeric motor and tail domains at both ends of a bipolar minifilament. Here, we describe regulatory mechanism involving direct binding between its fundamental role in microtubule sliding. tails decrease microtubule-stimulated ATP-hydrolysis specifically engaging the nucleotide-free or ADP states. Cryo-EM reveals that stabilizes an open domain ATP-active site. Full-length undergo slow...
Microtubule length control is essential for the assembly and function of mitotic spindle. Kinesin-like motor proteins that directly attenuate microtubule dynamics make key contributions to this control, but specificity these motors different subpopulations spindle microtubules not understood. Kif18A (kinesin-8) localizes plus ends relatively slowly growing kinetochore fibers (K-fibers) attenuates their dynamics, whereas Kif4A (kinesin-4) chromatin suppresses growth highly dynamic,...
Background: The mitotic kinesin, KIF18A, is required for proliferation of cancer cells that exhibit chromosome instability (CIN), implicating it as a promising target treatment subset aggressive tumor types. Determining regions the KIF18A protein to inhibition will be important design and optimization effective small molecule inhibitors. Methods: In this study, we used cultured cell models investigate effects mutating S284 within alpha-4 helix which was previously identified phosphorylated...
Abstract Malignant mesothelioma (MM) is an intractable tumor of the peritoneal and pleural cavities primarily linked to exposure asbestos. Recently, we described interplay between mitochondrial‐derived oxidants expression FOXM1, a redox‐responsive transcription factor that has emerged as promising therapeutic target in solid malignancies. Here have investigated effects nitroxides targeted mitochondria via triphenylphosphonium (TPP) moieties on mitochondrial oxidant production, FOXM1...
Micronuclei, whole or fragmented chromosomes spatially separated from the main nucleus, are associated with genomic instability and have been identified as drivers of tumorigenesis. Paradoxically, Kif18a mutant mice produce micronuclei due to asynchronous segregation unaligned in vivo but do not develop spontaneous tumors. We report here that form stable nuclear envelopes. Challenging via deletion Trp53 gene led formation thymic lymphoma elevated levels micronuclei. However, loss had modest...
The chromokinesin KIF22 generates forces that contribute to mitotic chromosome congression and alignment. Mutations in the α2 helix of motor domain have been identified patients with abnormal skeletal development, we report identification a patient novel mutation tail. We demonstrate pathogenic mutations do not result loss KIF22's functions early mitosis. Instead, disrupt segregation anaphase, resulting reduced proliferation, daughter cell nuclear morphology, and, subset cells, cytokinesis...
Significance Members of the kinesin superfamily serve a wide variety functions, and dominant narrative for these molecular motors has been that each member is uniquely specialized to very limited set functions. However, it now appreciated many members this group several distinct physiological roles, unclear how kinesins accomplish functional flexibility. In report, we describe posttranslational modification 5 family Eg5 dramatically alters its chemomechanical behavior make function much more...
Mitotic kinesins must be regulated to ensure a precise balance of spindle forces and accurate segregation chromosomes into daughter cells. Here, we demonstrate that kinesin-binding protein (KBP) reduces the activity KIF18A KIF15 during metaphase. Overexpression KBP disrupts movement alignment mitotic decreases length, combination phenotypes observed in cells deficient for KIF15, respectively. We show through gliding filament microtubule co-pelleting assays directly inhibits motor by...
Thioredoxin reductase (TR) catalyzes the reduction of thioredoxin (TRX), which in turn reduces mammalian typical 2-Cys peroxiredoxins (PRXs 1–4), thiol peroxidases implicated redox homeostasis and cell signaling. Typical PRXs are inactivated by hyperoxidation peroxidatic cysteine to cysteine-sulfinic acid, regenerated a two-step process involving retro-reduction sulfiredoxin (SRX) TRX. Here transient exposure menadione glucose oxidase was used examine dynamics oxidative inactivation...
Kinesin-binding protein inhibits kinesin activity through structural alterations of the motor domain.
KIF18A (kinesin-8) is required for mammalian mitotic chromosome alignment. confines movement to the spindle equator by accumulating at plus-ends of kinetochore microtubule bundles (K-fibers), where it functions suppress K-fiber dynamics. It not understood how motor accumulates plus-ends, a difficult feat requiring navigate protein dense tracks. Our data indicate that KIF18A's relatively long neck linker motor's accumulation plus-ends. Shorter (sNL) variants display deficiency in ends...