A5081758694- DNA Repair Mechanisms
- Pancreatic and Hepatic Oncology Research
- Phagocytosis and Immune Regulation
- Advanced Breast Cancer Therapies
- Cancer-related Molecular Pathways
- RNA modifications and cancer
- PARP inhibition in cancer therapy
- CRISPR and Genetic Engineering
- Microtubule and mitosis dynamics
- Carcinogens and Genotoxicity Assessment
- Radiation Therapy and Dosimetry
- Animal Nutrition and Physiology
- Mitochondrial Function and Pathology
- Ubiquitin and proteasome pathways
- Cancer therapeutics and mechanisms
- DNA and Nucleic Acid Chemistry
- Lung Cancer Treatments and Mutations
- Genomics and Chromatin Dynamics
- Cancer Genomics and Diagnostics
- Immunotherapy and Immune Responses
- RNA Interference and Gene Delivery
- Trace Elements in Health
- Protein Kinase Regulation and GTPase Signaling
- Genomics, phytochemicals, and oxidative stress
- Epigenetics and DNA Methylation
The University of Texas Southwestern Medical Center
2016-2025
Southwestern Medical Center
2010-2025
University of Georgia
2003-2021
Tygerberg Hospital
2021
Radiation Oncology Associates
2002-2015
South Australia Pathology
1997-2006
Cornell University
2005
University Health Network
2003
Princess Margaret Cancer Centre
2003
Australian Centre for HIV and Hepatitis Virology Research
1997
DNA double-stranded breaks (DSB) are among the most dangerous forms of damage. Unrepaired DSBs results in cells undergoing apoptosis or senescence whereas mis-processing can lead to genomic instability and carcinogenesis. One important pathway eukaryotic responsible for repair is non-homologous end-joining (NHEJ). In this review we will discuss interesting new insights into mechanism NHEJ proteins which mediate process. Furthermore, general role promoting stability be discussed.
Individual subunits of protein phosphatase 2A (PP2A), 4, and 5 were knocked out in Drosophila Schneider 2 cells by using RNA interference. Ablation either the scaffold (A) or catalytic (C) PP2A caused disappearance all subunits. Treating with double-stranded targeting four regulatory both A C The loss was associated decreased stability indicating that only heterotrimeric forms are stable intact cells. total against subunit, specific ablation R2/B enhanced insulin-induced ERK activation....
Ataxia telangiectasia mutated (ATM) plays a critical role in the cellular response to DNA damage. In double-strand breaks (DSBs), ATM is autophosphorylated at serine 1981. Although this autophosphorylation widely considered sign of activation, it still not clear if required for functions including localization DSBs and activation kinase activity. study, we show that differentially regulated with initial requiring MRE11-RAD50-NBS1 complex sustained retention Autophosphorylated interacts MDC1...
Multiple DNA double-strand break (DSB) repair pathways are active in S phase of the cell cycle; however, DSBs primarily repaired by homologous recombination (HR) this cycle phase. As non-homologous end-joining (NHEJ) factor, Ku70/80 (Ku), is quickly recruited to phase, we hypothesized that an orchestrated mechanism modulates pathway choice between HR and NHEJ via displacement Ku heterodimer from allow HR. Here, provide evidence phosphorylation at a cluster sites junction pillar bridge...
Abstract Pathway choice within DNA double-strand break (DSB) repair is a tightly regulated process to maintain genome integrity. RECQL4, deficient in Rothmund-Thomson Syndrome, promotes the two major DSB pathways, non-homologous end joining (NHEJ) and homologous recombination (HR). Here we report that RECQL4 coordinates NHEJ HR different cell cycle phases. interacts with Ku70 promote G1 when overall cyclin-dependent kinase (CDK) activity low. During S/G2 phases, CDK1 CDK2 (CDK1/2)...
Pancreatic ductal adenocarcinoma (PDAC) is notably resistant to conventional chemotherapy and radiation treatment. However, clinical trials indicate that carbon ion radiotherapy (CIRT) with concurrent gemcitabine effective for unresectable locally advanced PDAC. This study aimed identify patient characteristics predictive of CIRT response. We utilized a panel human PDAC cell lines diverse genetic profiles determine their sensitivity compared γ-rays, assessing relative biological...
Lung cancer exhibits altered metabolism, influencing its response to radiation. To investigate the metabolic regulation of radiation response, we conducted a comprehensive, metabolic-wide CRISPR-Cas9 loss-of-function screen using as selection pressure in human non–small cell lung cancer. Lipoylation emerged key target for radiosensitization, with lipoyltransferase 1 (LIPT1) identified top hit. LIPT1 covalently conjugates mitochondrial 2-ketoacid dehydrogenases lipoic acid, facilitating...
1. Since high concentrations of zinc are associated with reduced crop yields, environmental concerns emerging regarding accumulation in areas where poultry production is prevalent. This study investigates growth performance and utilisation during the life cycle broilers when diets were supplemented various from two different sources. 2. A total 740 Cobb 500 1-d-old male broiler chicks was randomly distributed into 88 battery cages. Excreta collected over a 48-h period on d 10, 17, 24, 31,...
The DNA damage response (DDR) encompasses the cellular to double-stranded breaks (DSBs), and includes recognition of DSB, recruitment numerous factors site, initiation signaling cascades, chromatin remodeling, cell-cycle checkpoint activation, repair DSB. Key drivers DDR are multiple members phosphatidylinositol 3-kinase-related kinase family, including ataxia telangiectasia mutated (ATM), Rad3-related (ATR), DNA-dependent protein catalytic subunit (DNA-PKcs). ATM ATR modulate portions DDR,...
DNA-PKcs is a key regulator of DNA double-strand break repair. Apart from its canonical role in the damage response, involved cellular response to oxidative stress (OS), but exact remains unclear. Here, we report that DNA-PKcs-deficient human cells display depolarized mitochondria membrane potential (MMP) and reoriented metabolism, supporting for phosphorylation (OXPHOS). directly interacts with proteins ANT2 VDAC2, formation DNA-PKcs/ANT2/VDAC2 (DAV) complex supports optimal exchange ADP...
Abstract Therapy resistance and metastatic progression are primary causes of cancer-related mortality. Disseminated tumor cells possess adaptive traits that enable them to reprogram their metabolism, maintain stemness, resist cell death, facilitating persistence drive recurrence. The survival disseminated also depends on ability modulate replication stress in response therapy while colonizing inhospitable microenvironments. In this study, we discovered the nuclear translocation AXL, a TAM...
Triple-negative breast cancer (TNBC) is a highly aggressive form of subtype often treated with radiotherapy (RT). Due to its intrinsic heterogeneity and lack effective targets, it crucial identify novel molecular targets that would increase RT efficacy. Here we demonstrate the role BUB1 (cell cycle Ser/Thr kinase) in TNBC radioresistance offer strategy improve treatment. Gene expression analysis was performed look at genes upregulated patient samples compared other subtypes. Cell...
DNA double strand breaks (DSB) are repaired by nonhomologous end-joining (NHEJ) or homologous recombination (HR). Recent genetic data in yeast shows that the choice between these two pathways for repair of DSBs is via competition NHEJ protein, Ku, and HR Mre11/Rad50/Xrs2 (MRX) complex. To study interrelationship human Ku Mre11 Mre11/Rad50 (MR), we established an vitro end resection system using a forked model dsDNA substrate purified Ku70/80, Mre11, Mre11/Rad50, exonuclease 1 (Exo1). Our...
The DNA damage response (DDR) is a complex signaling network that leads to repair while modulating numerous cellular processes. double-strand breaks (DSBs), highly cytotoxic lesion, activate this system most vigorously. DSB orchestrated by the ATM protein kinase, which phosphorylates key players in its various branches. Proteasome-mediated degradation plays an important role proteome dynamics following induction. Here, we identify nuclear proteasome activator PA28γ (REGγ; PSME3) as novel DDR...
Abstract Cancer testis antigens (CTA) are expressed in and placenta anomalously activated a variety of tumors. The mechanistic contribution CTAs to neoplastic phenotypes remains largely unknown. Using chemigenomics approach, we find that the CTA HORMAD1 correlates with resistance mitochondrial complex I inhibitor piericidin A non–small cell lung cancer (NSCLC). Resistance was due reductive intracellular environment attenuated accumulation free radicals. In human adenocarcinoma (LUAD) tumors,...
Mechanistic studies in DNA repair have focused on roles of multi-protein complexes, so how long non-coding RNAs (lncRNAs) regulate is less well understood. Yet, lncRNA LINP1 over-expressed multiple cancers and confers resistance to ionizing radiation chemotherapeutic drugs. Here, we unveil structural mechanistic insights into LINP1's ability facilitate non-homologous end joining (NHEJ). We characterized structure flexibility analyzed interactions with the NHEJ factor Ku70/Ku80 (Ku) Ku...
Ataxia-telangiectasia mutated (ATM) drives the DNA damage response via modulation of multiple signal transduction and repair pathways. Previously, ATM activity was implicated in promoting non-homologous end joining (NHEJ) pathway to a subset double-stranded breaks (DSBs), but how performs this function is still unclear. In study, we identified that phosphorylates DNA-dependent protein kinase catalytic subunit (DNA-PKcs), core NHEJ factor, at its extreme C-terminus threonine 4102 (T4102)...