A5071017326- Quantum Chromodynamics and Particle Interactions
- Particle physics theoretical and experimental studies
- Particle Accelerators and Free-Electron Lasers
- High-Energy Particle Collisions Research
- Particle Detector Development and Performance
- Photocathodes and Microchannel Plates
- Radiation Detection and Scintillator Technologies
- Cancer, Lipids, and Metabolism
- Genomics and Chromatin Dynamics
- Gyrotron and Vacuum Electronics Research
- Drug Transport and Resistance Mechanisms
- Particle accelerators and beam dynamics
- Atomic and Subatomic Physics Research
- Ferroptosis and cancer prognosis
- SARS-CoV-2 and COVID-19 Research
- Superconducting Materials and Applications
- interferon and immune responses
- RNA Research and Splicing
- Telomeres, Telomerase, and Senescence
- Nuclear physics research studies
- Cancer-related Molecular Pathways
- Ubiquitin and proteasome pathways
- DNA Repair Mechanisms
- Electron and X-Ray Spectroscopy Techniques
- Epigenetics and DNA Methylation
University of Pennsylvania
2013-2025
High Throughput Biology (United States)
2017-2024
California University of Pennsylvania
2024
Philadelphia University
2013-2023
Hamline University
2017-2023
Xilinx (United States)
2002-2020
The Wistar Institute
2005-2017
Istituto Nazionale Genetica Molecolare
2015
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
2015
Metabolon (United States)
2015
Posttranslational modification of histones has emerged as a key regulatory signal in eukaryotic gene expression. Recent genetic and biochemical studies link H3-lysine 9 (H3-K9) methylation to HP1-mediated heterochromatin formation silencing. However, the mechanisms that target coordinate these activities specific genes is poorly understood. Here we report KAP-1 corepressor for KRAB-ZFP superfamily transcriptional silencers binds SETDB1, novel SET domain protein with histone H3-K9-specific...
Macromolecular complexes containing histone deacetylase and ATPase activities regulate chromatin dynamics are vitally responsible for transcriptional gene silencing in eukaryotes. The mechanisms that target these assemblies to specific loci not as well understood. We show the corepressor KAP-1, via its PHD ( p lant h omeo d omain) bromodomain, links superfamily of Krüppel associated box (KRAB) zinc finger proteins (ZFP) NuRD complex. demonstrate tandem bromodomain an arrangement often found...
There is an urgent need for antivirals to treat the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To identify new candidates, we screen a repurposing library of ∼3,000 drugs. Screening in Vero cells finds few antivirals, while screening human Huh7.5 validates 23 diverse antiviral Extending our studies lung epithelial cells, find that there are major differences drug sensitivity and entry pathways used by SARS-CoV-2 these cells. Entry Calu-3 pH independent...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic, resulting millions of infections and deaths with few effective interventions available. Here, we demonstrate that SARS-CoV-2 evades interferon (IFN) activation in epithelial cells, delayed response bystander cells. Since pretreatment IFNs can block viral infection, reasoned pharmacological innate immune pathways could control infection. To identify potent antiviral agonists, screened panel 75 microbial...
The main protease (Mpro) of SARS-CoV-2 is a validated antiviral drug target. Several Mpro inhibitors have been reported with potent enzymatic inhibition and cellular activity, including GC376, boceprevir, calpain II, XII, each containing reactive warhead that covalently modifies the catalytic Cys145. Coupling structure-based design one-pot Ugi four-component reaction, we discovered one most noncovalent inhibitors, 23R (Jun8-76-3A) structurally distinct from canonical inhibitor GC376....
Krüppel-associated box (KRAB) domains are present in approximately one-third of all human zinc finger proteins (ZFPs) and potent transcriptional repression modules. We have previously cloned a corepressor for the KRAB domain, KAP-1, which is required KRAB-mediated vivo. To characterize mechanism utilized by we analyzed ability KAP-1 to interact with murine (M31 M32) (HP1alpha HP1gamma) homologues HP1 protein family, class nonhistone heterochromatin-associated well-established epigenetic gene...
Heterochromatin protein 1 (HP1) is a key component of constitutive heterochromatin in Drosophila and required for stable epigenetic gene silencing classically observed as position effect variegation. Less known the family mammalian HP1 proteins, which may be euchromatic, targeted to expressed loci by repressor-corepressor complexes, retained there Lys 9-methylated histone H3 (H3-MeK9). To characterize physical properties euchromatic bound HP1, we developed strategy regulated recruitment an...
KAP1/TIF1 is proposed to be a universal corepressor protein for the KRAB zinc finger (KRAB-zfp) superfamily of transcriptional repressors.To characterize role KAP1 and KAP1-interacting proteins in repression, we investigated regulation stably integrated reporter transgenes by hormoneresponsive repressor proteins.Here, demonstrate that depletion endogenous levels small interfering RNA (siRNA) significantly inhibited KRAB-mediated repression chromatin template.Similarly, reduction cellular...
Abstract During infection of macrophages, prolonged signaling by Mycobacterium tuberculosis (Mtb) or its 19-kDa lipoprotein (LpqH; Rv3763) inhibits IFN-γ-induced expression several immune function genes, including class II transactivator (CIITA), which regulates MHC. Mtb does not inhibit early IFN-γ events, e.g., Stat1α activation. This study analyzed downstream mechanisms that regulate the transcription MHC2TA, gene encoding CIITA. Chromatin immunoprecipitation showed induced acetylation...
Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation gain melanoma from patient who progressed on the inhibitor trametinib did not respond to dabrafenib. also identified same along with amplification xenograft tumor derived second resistant combination of dabrafenib trametinib. Melanoma cells chronically exposed acquired concurrent BRAF-V600E amplification, which conferred resistance inhibitors....
Zika virus is an emerging arthropod-borne flavivirus for which there are no vaccines or specific therapeutics. We screened a library of 2,000 bioactive compounds their ability to block infection in three distinct cell types with two different strains virus. Using microscopy-based assay, we validated 38 drugs that inhibited infection, including FDA-approved nucleoside analogs. Cells expressing high levels the attachment factor AXL can be protected from receptor tyrosine kinase inhibitors,...
As a multifunctional protein, KRAB domain-associated protein 1 (KAP1) is reportedly subjected to multiple posttranslational modifications, including phosphorylation and sumoylation. However, gaps exist in our knowledge of how KAP1 cross-talks with sumoylation what the biological consequence is. Here, we show that doxorubicin (Dox) treatment induces at Ser-824 via an ataxia telangiectasia mutated (ATM)-dependent manner, correlating transcriptional de-repression p21WAF1/CIP1 Gadd45alpha. A...