A5036287553- DNA Repair Mechanisms
- Telomeres, Telomerase, and Senescence
- Advanced NMR Techniques and Applications
- Electron Spin Resonance Studies
- Advanced MRI Techniques and Applications
- Spectroscopy and Quantum Chemical Studies
- Mitochondrial Function and Pathology
- Genomics and Chromatin Dynamics
- Genetics and Neurodevelopmental Disorders
- PARP inhibition in cancer therapy
- Advanced biosensing and bioanalysis techniques
- Genetics, Aging, and Longevity in Model Organisms
- Microtubule and mitosis dynamics
- Cerebrovascular and Carotid Artery Diseases
- Molecular Biology Techniques and Applications
- nanoparticles nucleation surface interactions
- Advanced Thermodynamics and Statistical Mechanics
- Solid-state spectroscopy and crystallography
- Cancer-related Molecular Pathways
- Protein Structure and Dynamics
- Cardiac Imaging and Diagnostics
- CRISPR and Genetic Engineering
- Phase Equilibria and Thermodynamics
- Coronary Interventions and Diagnostics
- Polysaccharides Composition and Applications
UPMC Hillman Cancer Center
2018-2025
University of Kansas Medical Center
2025
University of Pittsburgh
2019-2024
University of California, Santa Barbara
2013-2020
Pennsylvania State University
2014-2019
Penn State Milton S. Hershey Medical Center
2017-2019
Abstract Complex coacervation driven liquid-liquid phase separation (LLPS) of biopolymers has been attracting attention as a novel in living cells. Studies LLPS this context are typically proteins harboring chemical and structural complexity, leaving unclear which properties fundamental to complex versus protein-specific. This study focuses on the role polyethylene glycol (PEG)—a widely used molecular crowder—in LLPS. Significantly, entropy-driven is recapitulated with charged polymers...
PrimPol is a recently identified polymerase involved in eukaryotic DNA damage tolerance, employed both re-priming and translesion synthesis mechanisms to bypass nuclear mitochondrial lesions. In this report, we investigate how the enzymatic activities of human are regulated. We show that, unlike other TLS polymerases, not stimulated by PCNA does interact with it vivo. identify that interacts major single-strand binding proteins, RPA mtSSB Using NMR spectroscopy, characterize domains...
Abstract Oxidative stress is a primary cause of cellular senescence and contributes to the etiology numerous human diseases. damage telomeric DNA has been proposed premature by accelerating telomere shortening. Here, we tested this model directly using precision chemoptogenetic tool produce common lesion 8-oxo-guanine (8oxoG) exclusively at telomeres in fibroblasts epithelial cells. A single induction 8oxoG sufficient trigger multiple hallmarks p53-dependent senescence. Telomeric activates...
UV-DDB, consisting of subunits DDB1 and DDB2, recognizes UV-induced photoproducts during global genome nucleotide excision repair (GG-NER). We recently demonstrated a noncanonical role UV-DDB in stimulating base (BER) which raised several questions about the timing arrival at 8-oxoguanine (8-oxoG), dependency on recruitment downstream BER NER proteins. Using two different approaches to introduce 8-oxoG cells, we show that DDB2 is recruited immediately after damage colocalizes with...
Water dynamics in the hydration shell of peripheral membrane protein annexin B12 were studied using MD simulations and Overhauser DNP-enhanced NMR. We show that retardation water motions near phospholipid bilayers is extended by presence a membrane-bound protein, up to around 10 Å above protein. Near surface, electrostatic interactions with lipid head groups strongly slow down dynamics, whereas protein-induced weaker dominates only at distances beyond from surface. The results can be...
Hydration water on the surface of a protein is thought to mediate thermodynamics protein-ligand interactions. For hydration play role beyond modulating global solubility or stability, thermodynamic properties must reflect heterogeneous and thus spatially vary over surface. A potent read-out local variations in its equilibrium dynamics spanning picosecond nanosecond time scales. In this study, we employ Overhauser dynamic nuclear polarization (ODNP) probe at select sites Chemotaxis Y (CheY)...
Cancer cells maintain telomeres by upregulating telomerase or alternative lengthening of (ALT) via homology-directed repair at telomeric DNA breaks. 8-Oxoguanine (8oxoG) is a highly prevalent endogenous lesion in sequences, altering telomere structure and activity, but its impact on ALT unclear. Here, we demonstrate that targeted 8oxoG formation stimulates activity homologous recombination specifically cancer cells. Mechanistically, an acute induction increases replication stress, as...
Common fragile sites (CFSs) are genomic regions that display gaps and breaks in human metaphase chromosomes under replication stress often deleted cancer cells. We studied an ∼300-bp subregion (Flex1) of CFS FRA16D yeast found it recapitulates characteristics fragility Flex1 is dependent on the ability a variable-length AT repeat to form cruciform structure stalls replication. Fragility at initiated by structure-specific endonuclease Mus81-Mms4 acting together with Slx1-4/Rad1-10 complex,...
Abstract Mitochondrial dysfunction plays an important role in the aging process. However, mechanism by which this causes is not fully understood. The accumulation of mutations mitochondrial genome (or “mtDNA”) has been proposed as a contributor. One compelling piece evidence support hypothesis comes from Polg D257A/D257A mutator mouse ( mut/mut ). These mice express error‐prone DNA polymerase that results mtDNA mutations, accelerated aging, and premature death. In paper, we have used model...
Abstract Telomeres are hypersensitive to the formation of common oxidative lesion 8-oxoguanine (8oxoG), which impacts telomere stability and function. OGG1 MUTYH glycosylases initiate base excision repair (BER) remove 8oxoG or prevent mutation. Here, we show loss inhibition, loss, partially rescues telomeric 8oxoG-induced premature senescence associated proinflammatory responses, while both causes a near complete rescue in human fibroblasts. Glycosylase deficiency also suppresses fragility...
Abstract Oxidative stress is when cells experience more reactive oxygen species (ROS) than their antioxidant defenses can handle. ROS are generated by metabolic processes, environmental toxins, and radiation. react with guanine nucleotides produce one of the most common physiologic forms DNA damage, 8-oxo-guanine (8oxoG). The increased level highly linked to development cancer due oxidation. reaction a variety lesions, such as base alterations, strand breaks, cross-linking, which, if not...
: Neoplastic transformation and genome instability are enhanced by replication stress, conditions that slow or stall DNA forks. Consequently, cancer cells require multiple enzymes checkpoint signaling pathways to mitigate stress for their viability proliferation. Targeting proteins enhance cell survival during is a recent approach in clinical strategies, especially when targets produce synthetic lethality. polymerase eta (Pol η) has many key functions stability, particularly translesion...
Abstract The telomere specific shelterin complex, which includes TRF1, TRF2, RAP1, TIN2, TPP1 and POT1, prevents spurious recognition of telomeres as double-strand DNA breaks regulates telomerase repair activities at telomeres. TIN2 is a key component the complex that directly interacts with TRF2 TPP1. In vivo, large majority TRF1 are in but without POT1. Since knockdown also removes from telomeres, previous cell-based assays only provide information on downstream effects after loss...
Telomeres are prone to formation of the common oxidative lesion 8-oxoguanine (8oxoG), and acute production 8oxoG damage at telomeres is sufficient drive rapid cellular senescence. OGG1 MUTYH glycosylases initiate base excision repair (BER) sites remove or prevent mutation. Here, we show loss inhibition, loss, partially rescues telomeric 8oxoG-induced senescence, both results in a near complete rescue. Loss these also suppresses telomere fragility dysfunction, indicating that single-stranded...