A5033774057- Microtubule and mitosis dynamics
- Cancer-related Molecular Pathways
- Advanced Breast Cancer Therapies
- Cancer, Hypoxia, and Metabolism
- Genomics and Chromatin Dynamics
- Epigenetics and DNA Methylation
- Cancer Genomics and Diagnostics
- Chromosomal and Genetic Variations
- Mechanisms of cancer metastasis
- MicroRNA in disease regulation
- Glioma Diagnosis and Treatment
- Pluripotent Stem Cells Research
- DNA Repair Mechanisms
- Genomic variations and chromosomal abnormalities
- Cancer Cells and Metastasis
- Photosynthetic Processes and Mechanisms
- Ubiquitin and proteasome pathways
- RNA modifications and cancer
- RNA Research and Splicing
- Pancreatic function and diabetes
- CRISPR and Genetic Engineering
- Genetic and Kidney Cyst Diseases
- RNA and protein synthesis mechanisms
- Single-cell and spatial transcriptomics
- Renal and related cancers
Dartmouth College
2014-2024
Dartmouth Cancer Center
2023-2024
USC Norris Comprehensive Cancer Center
2015-2018
Cotton (United States)
2015-2018
Dartmouth–Hitchcock Medical Center
2015-2016
Palo Alto University
2009
Stanford University
2009
Bates College
2003
Abstract Centromeres are specified epigenetically through the deposition of centromere-specific histone H3 variant CENP-A. However, how additional epigenetic features involved in centromere specification is unknown. Here, we find that H4 Lys5 and Lys12 acetylation (H4K5ac H4K12ac) primarily occur within pre-nucleosomal CENP-A–H4–HJURP (CENP-A chaperone) complex, before deposition. We show H4K5ac H4K12ac mediated by RbAp46/48–Hat1 complex RbAp48-deficient DT40 cells fail to recruit HJURP...
Abstract Tumors are dynamic organs that evolve during disease progression with genetic, epigenetic, and environmental differences among tumor cells serving as the foundation for selection evolution in tumors. Tumor-initiating (TIC) responsible tumorigenesis a source of functional cellular heterogeneity, whereas chromosomal instability (CIN) is karyotypic genetic diversity. However, extent CIN contributes to TIC diversity its relationship function remains unclear. Here, we demonstrate...
Intra-tumor heterogeneity stems from genetic, epigenetic, functional, and environmental differences among tumor cells. A major source of genetic comes DNA sequence and/or whole chromosome focal copy number variations (CNVs). Whole CNVs are caused by chromosomal instability (CIN) that is defined a persistently high rate mis-segregation. Accordingly, CIN causes constantly changing karyotypes result in extensive cell-to-cell heterogeneity. How the influences gene expression individual cells...
Aneuploidy is frequently detected in human cancers and implicated carcinogenesis. Pharmacologic targeting of aneuploidy an attractive therapeutic strategy, as this would preferentially eliminate malignant over normal cells. We previously discovered that CDK2 inhibition causes lung cancer cells with more than two centrosomes to undergo multipolar cell division leading apoptosis, defined anaphase catastrophe. Cells activating KRAS mutations were especially sensitive inhibition. Mechanisms...
Despite advances in targeted therapy, lung cancer remains the most common cause of cancer-related mortality United States. Chromosomal instability is a prominent feature and, because it rarely occurs normal cells, represents potential therapeutic target. Our prior work discovered that cells undergo anaphase catastrophe response to inhibition cyclin-dependent kinase 2 (CDK2), followed by apoptosis and reduced growth. In this study, effects mechanisms multi-CDK inhibitor dinaciclib on were...
During in vitro propagation, human pluripotent stem cells (hPSCs) frequently become aneuploid with incorrect chromosome numbers due to mitotic segregation errors. Yet, it is not understood why hPSCs exhibit a low fidelity. Here, we investigate the mechanisms responsible for errors and show that primary cause lagging chromosomes anaphase improper merotelic microtubule attachments. Accordingly, short-term treatment (<24 h) small molecules prolong duration or destabilize attachments reduces...
Chromosomal instability (CIN) is a hallmark of solid tumor biology and implicated in carcinogenesis. Preferentially eliminating malignant cells by targeting CIN aneuploidy an attractive antineoplastic strategy. We previously reported that CDK2 antagonism causes lung cancer to undergo anaphase catastrophe apoptosis through inhibition phosphorylation the centrosomal protein CP110. Cells with activating KRAS mutations were particularly sensitive due downregulation CP110 levels. This study...
Kinetochore protein phosphorylation promotes the correction of erroneous microtubule attachments to ensure faithful chromosome segregation during cell division. Determining how executes error requires an understanding whether kinetochore substrates are completely (i.e., all-or-none) or only fractionally phosphorylated. Using quantitative mass spectrometry (MS), we measured phospho-occupancy on conserved Hec1 (NDC80) that directly binds microtubules. None positions exceeded ∼50%...
Human pluripotent stem cells (hPSCs) maintain diploid populations for generations despite a persistently high rate of mitotic errors that cause aneuploidy, or chromosome imbalances. Consequently, to genome stability, aneuploidy must inhibit hPSC proliferation, but the mechanisms are unknown. Here, we surprisingly find homogeneous aneuploid hPSCs proliferate unlike non-transformed somatic cells. Instead, in mosaic populations, cell non-autonomous competition between neighboring and eliminates...
To ensure genomic fidelity, a series of spatially and temporally coordinated events is executed during prometaphase mitosis, including bipolar spindle formation, chromosome attachment to microtubules at kinetochores, the correction erroneous kinetochore-microtubule (k-MT) attachments, congression equator. Cyclin A/Cdk1 kinase plays key role in destabilizing k-MT attachments promote attachments. However, it unknown whether regulates other prometaphase. Here, we investigate additional roles by...
Expression of sigma(s), the gene product rpoS, is controlled translationally in response to many environmental stresses. DsrA, a small 87-nucleotide non-coding RNA molecule, acts increase translational efficiency RpoS mRNA under some growth conditions. In this work, we demonstrate that DsrA binds directly 30 S ribosomal subunit with an observed equilibrium affinity 2.8 x 10(7) m(-1). does not compete or tRNA(f)(Met) for binding subunit. The 5' end subunits association constant 2.0 10(6)...
Summary Kinetochore protein phosphorylation promotes the correction of erroneous microtubule attachments to ensure faithful chromosome segregation during cell division. Determining how executes error requires an understanding whether kinetochore substrates are completely (i.e. all-or-none) or only fractionally phosphorylated. Using quantitative mass spectrometry (MS), we measured phospho-occupancy on conserved Hec1 (NDC80) that directly binds microtubules. None positions exceeded ∼50%...
Abstract Aneuploidy is frequently detected in human cancers and implicated carcinogenesis. Whether aneuploidy an anti-neoplastic target remains to be learnt. We previously uncovered unrecognized consequence of Cdk2 inhibition that causes lung cancer cells undergo anaphase catastrophe, growth apoptosis. Cells with activating KRAS mutations were especially sensitive inhibition. The mechanism Cdk2-mediated catastrophe how activated promotes this effect was the subject study. Live-cell imaging...
<p>Supplemental Fig. S4. (A) Effect of engineered KRAS expression on response to CDK2 inhibition by seliciclib. mutation sensitized lung cancer cells towards seliciclib-mediated growth as compared control-ED-1 cells. (B) Cells transfected with the plasmid expressing HA-tagged human CP110 were used for detection using an anti-CP110 antibody (1:1000) and anti-HA (1:1000), respectively. The upper band detected specifically recognizes CP110. (C) Respective RAS protein profile in murine...
<p>Supplemental Fig. S3. (A) Schematic diagram showing the relationship between CDK2, CP110, activated KRAS and anaphase catastrophe. (B) Engineered overexpression of CP110 was detected in A549, Hop62, H522 H460 cells (versus control transfectants) using anti-HA antibody after 24 48 hours transfection. A representative immunoblot for each cell line is displayed.</p>
<div>Abstract<p>Aneuploidy is frequently detected in human cancers and implicated carcinogenesis. Pharmacologic targeting of aneuploidy an attractive therapeutic strategy, as this would preferentially eliminate malignant over normal cells. We previously discovered that CDK2 inhibition causes lung cancer cells with more than two centrosomes to undergo multipolar cell division leading apoptosis, defined anaphase catastrophe. Cells activating <i>KRAS</i> mutations were...
<div>Abstract<p>Aneuploidy is frequently detected in human cancers and implicated carcinogenesis. Pharmacologic targeting of aneuploidy an attractive therapeutic strategy, as this would preferentially eliminate malignant over normal cells. We previously discovered that CDK2 inhibition causes lung cancer cells with more than two centrosomes to undergo multipolar cell division leading apoptosis, defined anaphase catastrophe. Cells activating <i>KRAS</i> mutations were...
<p>Supplemental Fig. S5. Representative CP110 immunohistochemistry staining of lung normal (N) versus malignant (T) tissues harvested independently from KRAS wild-type transgenic mice and mutant mice.The table displays mutation information, scoring intensity immunostaining in 6 cancer specimens cyclin-E Kras LSL-G12D driven engineered respectively.</p>
<p>Supplemental Fig. S1. Effect of wild-type or a phosphorylation sites mutant CP110 species on responses to CDK2 inhibition. (A) Overexpression was detected in ED-1 cells with an anti-HA antibody 24 and 48 hours after transfection. (B) significantly reduced apoptosis induced by seliciclib treatment. overexpressing were treated the indicated dosages for analyzed apoptosis. (C D). phosphorylation-site mutated did not have significant effect anaphase catastrophe mutant-CP110 transfected...
<p>Supplemental File S1. The siRNA sequences and real-time qPCR primer sequences.</p>
<p>Supplemental File S2. A representative video of a Hop62 cell that undergoes multipolar division.</p>