A5101739206- Telomeres, Telomerase, and Senescence
- DNA Repair Mechanisms
- Genomics and Chromatin Dynamics
- Protein Degradation and Inhibitors
- RNA Research and Splicing
- Cancer therapeutics and mechanisms
- Acute Myeloid Leukemia Research
- Cancer-related Molecular Pathways
- CRISPR and Genetic Engineering
- PARP inhibition in cancer therapy
- Chromosomal and Genetic Variations
- Histone Deacetylase Inhibitors Research
- RNA modifications and cancer
- Epigenetics and DNA Methylation
- Ubiquitin and proteasome pathways
- Microplastics and Plastic Pollution
- Plant Molecular Biology Research
- Microtubule and mitosis dynamics
- Bacteriophages and microbial interactions
- DNA and Nucleic Acid Chemistry
- Neurobiology and Insect Physiology Research
- Cancer-related gene regulation
- Silicon Effects in Agriculture
- Operations Management Techniques
- Viral-associated cancers and disorders
Memorial Sloan Kettering Cancer Center
2012-2025
Kettering University
2022
University of Nebraska Medical Center
2012-2021
Bucheon University
2021
Soonchunhyang University
2021
New York Proton Center
2015
Molecular Biology Consortium
2015
Cornell University
2010
University of Nebraska at Omaha
2009
Yonsei University
1998-2005
Telomere homeostasis is regulated by telomerase and a collection of associated proteins. Telomerase is, in turn, post-translational modifications the rate-limiting catalytic subunit hTERT. Here we show that disruption Hsp90 geldanamycin promotes efficient ubiquitination proteasome-mediated degradation Furthermore, have used yeast two-hybrid method to identify novel RING finger gene ( MKRN1 ) encoding an E3 ligase mediates Overexpression telomerase-positive cells hTERT decreases activity...
Abstract Nucleolytic resection of DNA ends is critical for homologous recombination, but its mechanism not fully understood, particularly in mammalian meiosis. Here we examine roles the conserved MRN complex (MRE11, RAD50, and NBS1) through genome-wide analysis meiotic during spermatogenesis mice with various mutations, including several that cause chromosomal instability humans. Meiotic DSBs form at elevated levels remain unresected if Mre11 conditionally deleted, thus required both...
Poly(ADP-ribose) polymerases (PARPs) catalyze the transfer of multiple adenine diphosphate ribose (ADP-ribose) units from nicotinamide dinucleotide (NAD) to substrate proteins. There are 17 PARPs in humans. Several PARPs, such as PARP-1 and Tankyrase-1, known play important roles DNA repair, transcription, mitosis, telomere length maintenance. To better understand functions at a molecular level, it is necessary know what proteins modify. Here we report clickable NAD analogues that can be...
The cyclin-dependent kinases (CDKs) that promote cell-cycle progression are targets for negative regulation by signals from damaged or unreplicated DNA, but also play active roles in response to DNA lesions. requirement activity the face of damage implies there mechanisms insulate certain CDKs checkpoint inhibition. It remains difficult, however, assign precise functions specific protecting genomic integrity. In mammals, Cdk2 is throughout S and G2 phases, protein dispensable survival, owing...
PGBD5 DNA transposase confers therapeutically actionable dependency in solid tumors.
We have identified a rice gene encoding DNA-binding protein that specifically recognizes the telomeric repeat sequence TTTAGGG found in plants. This gene, which we refer to asRTBP1 (rice telomere-binding 1), encodes polypeptide with predicted molecular mass of 70 kDa. RTBP1 is ubiquitously expressed various organs and binds DNA two or more duplex repeats. The includes single domain at C terminus extensive homology Myb-like binding motif. very closely related other proteins, including TRF1,...
The Mre11 complex (Mre11, Rad50, and Nbs1) is integral to both DNA repair ataxia telangiectasia mutated (ATM)-dependent damage signaling. All three components are essential for viability at the cellular organismal levels. To delineate non-essential functions that mediated by Nbs1, we used TALEN-based genome editing derive Nbs1 mutant mice (Nbs1mid mice), which harbor mutations in interaction domain of Nbs1. Nbs1mid alleles abolished were incompatible with viability. Conversely, a...
Telomerase activity is expressed in most types of cancer cells but not normal somatic cells, suggesting that telomerase may be an important target for chemotherapy. Inhibition results telomere erosion, leading to the subsequent growth arrest followed by senescence or cell death. In this study, we screened a chemical library inhibition human telomerase, identifying three inhibitors. All compounds contained common nitrostyrene moiety conjugated different side chains. One these compounds,...
Telomere maintenance is essential for the continued proliferation of dividing cells, and implicated in chromosome stability cell immortalization. Telomerase activity allows cells to maintain their telomeric DNA contributes indefinite replicative capacity cancer cells. expressed most but not normal somatic suggesting that telomerase an attractive target chemotherapy. Here we screened a chemical library inhibition human telomerase, identified 2,3,7-trichloro-5-nitroquinoxaline (TNQX) as potent...
ABSTRACT Nucleolytic resection of DNA ends is critical for homologous recombination, but its mechanism not fully understood, particularly in mammalian meiosis. Here we examine roles the conserved MRN complex (MRE11, RAD50, and NBS1) through genome-wide analysis meiotic mice with various mutations, including several that cause chromosomal instability humans. Meiotic DSBs form at elevated levels remain unresected if Mre11 conditionally deleted, thus required both initiation regulation DSB...
Uncontrolled proliferation is one of the hallmarks breast cancer. We have previously identified human Ecd protein (human ortholog Drosophila Ecdysoneless, hereafter called Ecd) as a novel promoter mammalian cell cycle progression, function related to its ability remove repressive effects Rb-family tumor suppressors on E2F transcription factors. Given frequent dysregulation regulatory components in cancer, we used immunohistochemistry paraffin-embedded tissues examine expression normal tissue...
Ecdysoneless (ECD) is an evolutionarily conserved protein whose germ line deletion embryonic lethal. Deletion of Ecd in cells causes cell cycle arrest, which rescued by exogenous ECD, demonstrating a requirement ECD for normal mammalian progression. However, the exact mechanism regulates unknown. Here, we demonstrate that levels and subcellular localization are invariant during progression, suggesting potential role posttranslational modifications or protein-protein interactions. Since...
RNase PH is a phosphate-dependent exoribonuclease that catalyzes the removal of nucleotides at 3′ end tRNA precursor, leading to release nucleoside diphosphate, and generates CCA during maturation process. The 1.9-Å crystal structures apo phosphate-bound forms from <i>Pseudomonas aeruginosa</i> reveal monomeric with an α/β-fold tightly associated into hexameric ring structure in form trimer dimers. A five ion pair network, Glu-63-Arg-74-Asp-116-Arg-77-Asp-118 ion-pair Glu-26-Arg-69 are...
The mammalian ortholog of Drosophila ecdysoneless (Ecd) gene product regulates Rb-E2F interaction and is required for cell cycle progression. Ecd overexpressed in breast cancer its overexpression predicts shorter survival patients with ErbB2-positive tumors. Here, we demonstrate knock down (KD) human mammary epithelial cells (hMECs) induces growth arrest, similar to the impact Knock out (KO) mouse embryonic fibroblasts. Furthermore, whole-genome mRNA expression analysis control vs. KD hMECs...
Significance The Mre11 complex core, consisting of Mre11, Rad50, and Nbn/Nbs1, is essential for viability. Accordingly, hematopoietic-specific Nbn deficiency leads to perinatal lethality. In contrast, destabilizing the interaction with core Mre11−Rad50 ( mid8 allele) in hematopoietic cells permits viability but severe defects hematopoiesis. Viability requires gene amplification MRE11 CHK1 . We propose that overexpression compensates weakened interaction, selection mitigates genomic...
The MRE11 complex (comprising MRE11, RAD50, and NBS1) is integral to the maintenance of genome stability. We previously showed that a hypomorphic Mre11 mutant mouse strain ( ATLD1/ATLD1 ) was highly susceptible oncogene-induced breast cancer. Here we used mammary organoid system examine which MRE11-dependent responses are tumor-suppressive. found organoids exhibited an elevated interferon-stimulated gene (ISG) signature sustained changes in chromatin accessibility. This phenotype depended on...
Ecdysoneless (Ecd) is an evolutionarily conserved protein and its function essential for embryonic development in Drosophila cell growth yeast. However, has remained unknown until recently. Studies yeast suggested a potential role of Ecd transcription; however, lacks DNA-binding domain. Using GAL4-luciferase reporter assay GAL4 domain fusion with or mutants, we present evidence that human transactivation activity C-terminal region. Importantly, further analyses using point mutants showed...
The mammalian orthologue of ecdysoneless (ECD) protein is required for embryogenesis, cell cycle progression, and mitigation endoplasmic reticulum stress. Here, we identified key components the mRNA export complexes as binding partners ECD characterized functional interaction with export-related DEAD BOX helicase DDX39A. We find that involved in RNA through its knockdown (KD) blocks from nucleus to cytoplasm, which rescued by expression full-length but not an mutant defective have previously...
Actively dividing cells show progressive loss of telomeric DNA during successive rounds replication due to end-replication problem. Telomere shortening has been proposed as a regulatory mechanism that controls the replicative capacity primary before undergoing cellular senescence. In immortal including cancer, senescence can be overcome by reactivation telomerase or telomerase-independent for lengthening telomeres. this work, we present novel example telomere elongation in human stomach...
The Mre11 complex (comprising Mre11, Rad50, Nbs1) is integral to the maintenance of genome stability. We previously showed that a hypomorphic