A5028455073- Microtubule and mitosis dynamics
- DNA Repair Mechanisms
- DNA and Nucleic Acid Chemistry
- Genomics and Chromatin Dynamics
- DNA and Biological Computing
- Ion Channels and Receptors
- Mitochondrial Function and Pathology
- Photosynthetic Processes and Mechanisms
- Chromosomal and Genetic Variations
- Nuclear Structure and Function
- Molecular Biology Techniques and Applications
- Cell death mechanisms and regulation
- Cancer Cells and Metastasis
- Postharvest Quality and Shelf Life Management
- Cancer Genomics and Diagnostics
- Cancer-related Molecular Pathways
- Advanced biosensing and bioanalysis techniques
- RNA and protein synthesis mechanisms
- Genetic and Kidney Cyst Diseases
- Genomic variations and chromosomal abnormalities
- Biomedical and Engineering Education
- Neurobiology and Insect Physiology Research
- Genetic factors in colorectal cancer
- RNA modifications and cancer
- Epigenetics and DNA Methylation
Yale University
2022-2025
Yale Cancer Center
2022-2024
Dartmouth College
2012-2017
Harvard University
2016-2017
Massachusetts General Hospital
2016-2017
Cotton (United States)
2012-2015
USC Norris Comprehensive Cancer Center
2012-2014
The ataxia telangiectasia mutated and Rad3-related (ATR) kinase is crucial for DNA damage replication stress responses. Here, we describe an unexpected role of ATR in mitosis. Acute inhibition or degradation mitosis induces whole-chromosome missegregation. effect ablation not due to altered cyclin-dependent 1 (CDK1) activity, responses, unscheduled synthesis but loss function at centromeres. In mitosis, localizes centromeres through Aurora A-regulated association with centromere protein F...
Many cancers display both structural (s-CIN) and numerical (w-CIN) chromosomal instabilities. Defective chromosome segregation during mitosis has been shown to cause DNA damage that induces rearrangements of chromosomes (s-CIN). In contrast, whether can disrupt mitotic processes generate whole instability is unknown. Here, we show activation the DNA-damage response (DDR) selectively stabilizes kinetochore-microtubule (k-MT) attachments through Aurora-A PLK1 kinases, thereby increasing...
TGF-β secreted by tumor stroma induces epithelial-to-mesenchymal transition (EMT) in cancer cells, a reversible phenotype linked to progression and drug resistance. However, exposure stromal signals may also lead heritable changes which are poorly understood. We show that epithelial cells failing undergo proliferation arrest during TGF-β-induced EMT sustain mitotic abnormalities due failed cytokinesis, resulting aneuploidy. This genomic instability is associated with the suppression of...
Accurate chromosome segregation during mitosis relies on a dynamic kinetochore (KT)–microtubule (MT) interface that switches from labile to stable condition in response correct MT attachments. This transition is essential satisfy the spindle-assembly checkpoint (SAC) and couple MT-generated force with movements, but underlying regulatory mechanism remains unclear. In this study, we show MT- KT-associated protein CLASP2 progressively distinctively phosphorylated by Cdk1 Plk1 kinases,...
The exquisite sensitivity of mitotic cancer cells to ionizing radiation (IR) underlies an important rationale for the widely used fractionated therapy. However, mechanism this cell cycle-dependent vulnerability is unknown. Here we show that treatment with IR leads chromosome segregation errors in vivo and long-lasting aneuploidy tumour-derived lines. These generate abundance micronuclei predispose chromosomes subsequent catastrophic pulverization thereby independently amplifying...
Correction of faulty kinetochore-microtubule attachments is essential for faithful chromosome segregation and dictated by the opposing activities Aurora B kinase PP1 PP2A phosphatases. How phosphatase are appropriately balanced less clear. Here, we show that a centromeric pool PP2A-B56 counteracts T-loop phosphorylation recruited to centromeres through Shugoshin-1 (Sgo1). In non-transformed RPE-1 cells, B, Sgo1, enriched on levels diminish as chromosomes establish bi-oriented attachments....
To gain insight into biological mechanisms that cause resistance to DNA damage, we performed parallel pooled genetic CRISPR-Cas9 screening for survival in high risk HNSCC subtypes. Surprisingly, and addition ATM, DNAPK, NFKB signaling, JAK1 was identified as a driver of tumor cell radiosensitivity. Knockout increases by enhancing the damage-induced G2 arrest, both knockout inhibition with abrocitinib prevent subsequent formation radiation-induced micronuclei. Loss function does not affect...
Mutations in the STAG2 gene are present ∼20% of tumors from different tissues origin. encodes a subunit cohesin complex, and with loss-of-function mutations usually aneuploid display elevated frequencies lagging chromosomes during anaphase. Lagging hallmark chromosomal instability (CIN) arising persistent errors kinetochore-microtubule (kMT) attachment. To determine whether loss increases rate formation kMT attachment or decreases their correction, we examined mitosis STAG2-deficient cells....
In mitosis, cells undergo a precisely orchestrated series of spatiotemporal changes in cytoskeletal structure to divide their genetic material. These are coordinated by sophisticated network protein–protein interactions and posttranslational modifications. this study, we report bifurcation signaling cascade the NIMA-related kinases (Neks) Nek6, Nek7, Nek9 that is required for localization function two kinesins essential cytokinesis, Mklp2 Kif14. We demonstrate Nek9, module controls timely...
Abstract A drastic TRPA1 mutant (R919*) identified in CRAMPT syndrome patients has not been mechanistically characterized. Here, we show that the R919* confers hyperactivity when co-expressed with wild type (WT) TRPA1. Using functional and biochemical assays, reveal co-assembles WT subunits into heteromeric channels heterologous cells are at plasma membrane. The hyperactivates by enhancing agonist sensitivity calcium permeability, which could account for observed neuronal...
Centromere protein A (CENP-A) defines centromere identity and nucleates kinetochore formation for mitotic chromosome segregation. Here, we show that ataxia telangiectasia Rad3-related (ATR) kinase, a master regulator of the DNA damage response, protects CENP-A occupancy at interphase centromeres in damage-independent manner. In unperturbed cells, ATR localizes to promyelocytic leukemia nuclear bodies (PML NBs), which house histone H3.3 chaperone DAXX (death domain-associated 6). We find...
Polo-like kinase 1 (PLK1) protects against genome instability by ensuring timely and accurate mitotic cell division, its activity is tightly regulated throughout the cycle. Although pathways that initially activate PLK1 in G2 are well-characterized, factors directly regulate remain poorly understood. Here, we identify human sustained DNA damage response Checkpoint 2 (Chk2) mitosis. Chk2 phosphorylates T210, a residue on T-loop whose phosphorylation essential for full activity. Loss of...
Ribosome biogenesis (RB) is an intricate and evolutionarily conserved process that takes place mainly in the nucleolus required for eukaryotic cells to maintain homeostasis, grow size, divide. Our laboratory has identified NUF2 protein, part of mitotic kinetochore, a genome-wide siRNA screen proteins making ribosomes MCF10A human breast epithelial (Farley-Barnes, 2018). After rigorous validation using several biochemical cell-based assays, we find role pre-rRNA transcription, primary...
Summary Polo-like kinase 1 (PLK1) protects against genome instability by ensuring timely and accurate mitotic cell division. PLK1 activity is tightly regulated throughout the cycle. Although pathways that initially activate in G2 are well-characterized, factors directly regulate mitosis remain poorly understood. Here, we identify human sustained DNA damage response Checkpoint 2 (Chk2) mitosis. Chk2 phosphorylates T210, a residue on its T-loop whose phosphorylation essential for full...
Supplementary Figure Legends from DNA-Damage Response during Mitosis Induces Whole-Chromosome Missegregation
<p>A, Immunoblots of control RPE1 cells and depleted for Chk2 using siRNA stained anti-Chk2 antibody anti-actin as a loading control. B, Chromosome mis-segregation in the presence or absence Doxorubicin. Bars represent mean, n = 150 cells, 3 experiments, **, p<0.01. C, AT22IJE-T fibroblasts expressing FLAG-ATM either Chloroquine (31μg ml-1) Doxorubicin (0.5 μM). p<0.01.</p>