A5012222286- DNA Repair Mechanisms
- Hearing, Cochlea, Tinnitus, Genetics
- Autophagy in Disease and Therapy
- Mitochondrial Function and Pathology
- Genetics and Neurodevelopmental Disorders
- Legal Issues in Turkey
- Calcium signaling and nucleotide metabolism
- Nuclear Receptors and Signaling
- CRISPR and Genetic Engineering
- PARP inhibition in cancer therapy
- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- Protein Kinase Regulation and GTPase Signaling
- Caveolin-1 and cellular processes
- Economic, Social, and Health Studies
- Plant Molecular Biology Research
- Working Capital and Financial Performance
- Ion Channels and Receptors
- Adenosine and Purinergic Signaling
- Fibroblast Growth Factor Research
- PI3K/AKT/mTOR signaling in cancer
- History and Cultural Heritage
- Metabolism, Diabetes, and Cancer
- Connexins and lens biology
- International Business and FDI
National Institute on Aging
2017-2024
National Institutes of Health
2017-2024
University of California, Irvine
2022
Institute on Aging
2020
University of Illinois Chicago
2009-2018
Augusta University
2018
Jesse Brown VA Medical Center
2018
University of Arizona
2018
Charlie Norwood VA Medical Center
2018
Al-Mustafa International University
2013
Abstract Metabolic dysfunction is a primary feature of Werner syndrome (WS), human premature aging disease caused by mutations in the gene encoding (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but underlying mechanisms are not understood, and whether deficit can be targeted for therapeutic intervention has been determined. Here we report impaired mitophagy depletion NAD + , fundamental ubiquitous molecule, patient samples invertebrate models. WRN regulates...
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)...
VEGFR2 (KDR/Flk1) signaling in endothelial cells (ECs) plays a central role angiogenesis. The P-type ATPase transporter ATP7A regulates copper homeostasis, and its angiogenesis is entirely unknown. Here, we describe the unexpected crosstalk between Copper ATP7A, autophagy, degradation. functional significance of this was demonstrated by finding that inducible EC-specific deficient mice or ATP7A-dysfunctional ATP7Amut showed impaired post-ischemic neovascularization. In ECs, loss inhibited...
Aging is a major risk factor for many types of cancer, and the molecular mechanisms implicated in aging, progeria syndromes, cancer pathogenesis display considerable similarities. Maintaining redox homeostasis, efficient signal transduction, mitochondrial metabolism essential genome integrity preventing progression to cellular senescence or tumorigenesis. NAD + central signaling molecule involved these other processes age-related diseases cancer. Growing evidence implicates decline as...
Abstract Age-related hearing loss (ARHL) is one of the most common disorders affecting elderly individuals. There an urgent need for effective preventive measures ARHL because none are currently available. Cockayne syndrome (CS) a premature aging disease that presents with progressive at young age, but otherwise similar to ARHL. two human genetic complementation groups CS, A and B. While clinical phenotypes in patients similar, proteins have very diverse functions, insight into their...
Members of the intersectin (ITSN) family scaffold proteins consist multiple modular domains, each with distinct ligand preferences. Although ITSNs were initially implicated in regulation endocytosis, subsequent studies have revealed a more complex role for these additional biochemical pathways. In this study, we performed high throughput yeast two-hybrid screen to identify pathways regulated by scaffolds. several known ITSN binding partners identified, isolated than 100 new targets two...
Abstract Cockayne Syndrome (CS) is a rare neurodegenerative disease characterized by short stature, accelerated aging and lifespan. Mutations in two human genes, ERCC8/CSA ERCC6/CSB, are causative for CS their protein products, CSA CSB, while structurally unrelated, play roles DNA repair other aspects of metabolism cells. Many clinical molecular features remain poorly understood, it was observed that CSB regulate transcription ribosomal (rDNA) genes ribosome biogenesis. Here, we investigate...
Copper transporter ATP7A (copper-transporting/ATPase) is required for full activation of SOD3 (extracellular superoxide dismutase), which secreted from vascular smooth muscle cells (VSMCs) and anchors to endothelial cell surface preserve function by scavenging extracellular superoxide. We reported that protein expression activity are decreased in insulin-deficient type 1 diabetes mellitus vessels, thereby, inducing superoxide-mediated dysfunction, rescued insulin treatment. However, it...
Abstract Cockayne syndrome (CS) is a rare premature aging disease, most commonly caused by mutations of the genes encoding CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations have an average life expectancy 12 years. The proteins are involved in transcription DNA repair, with latter including transcription‐coupled nucleotide excision repair (TC‐NER). However, there also evidence for mitochondrial dysfunction CS, which likely contributes to...
Age-related hearing loss (ARHL) is the most common sensory disability associated with human aging. Yet, there are no approved measures for preventing or treating this debilitating condition. With its slow progression, continuous and safe approaches critical ARHL treatment. Nicotinamide Riboside (NR), a NAD+ precursor, well tolerated even long-term use already shown effective in various disease models including Alzheimer's Parkinson's disease. It has also been beneficial against noise-induced...
Abstract Cockayne syndrome is an accelerated aging disorder, caused by mutations in the CSA or CSB genes. In CSB-deficient cells, poly (ADP ribose) polymerase (PARP) persistently activated unrepaired DNA damage and consumes depletes cellular nicotinamide adenine dinucleotide, which leads to mitochondrial dysfunction. Here, distribution of (PAR) was determined cells using ADPr-ChAP ribose-chromatin affinity purification), results show striking enrichment PAR at transcription start sites,...
There is considerable interest in whether sensory deficiency associated with the development of Alzheimer's disease (AD). Notably, relationship between hearing impairment and AD high relevance but still poorly understood. In this study, we found early-onset loss two mouse models, 3xTgAD 3xTgAD/Polβ
Caveolin-1 (Cav-1) is a scaffolding protein and major component of caveolae/lipid rafts. Previous reports have shown that endothelial dysfunction in Cav-1-deficient (Cav-1 −/− ) mice mediated by elevated oxidative stress through nitric oxide synthase (eNOS) uncoupling increased NADPH oxidase. Oxidant the net balance oxidant generation scavenging, role Cav-1 as regulator antioxidant enzymes vascular tissue poorly understood. Extracellular SOD (SOD3) copper (Cu)-containing enzyme secreted from...
Ubiquitylation of receptor tyrosine kinases plays a critical role in regulating the trafficking and lysosomal degradation these important signaling molecules. We identified multidomain scaffolding protein intersectin 1 (ITSN1) as an regulator this process (N. P. Martin et al., Mol. Pharmacol. 70:1463-1653, 2006) ITSN1 stimulates ubiquitylation epidermal growth factor (EGFR) through enhancing activity Cbl E3 ubiquitin ligase. However, precise mechanism which enhances was unclear. In study, we...
Ubiquitylation of receptor tyrosine kinases (RTKs) regulates their trafficking and lysosomal degradation. The multidomain scaffolding protein intersectin 1 (ITSN1) is an important regulator this process. ITSN1 stimulates ubiquitylation the epidermal growth factor (EGFR) through enhancing activity Cbl E3 ubiquitin ligase. However, precise mechanism which enhances unclear. Here, we demonstrate that interacts with recruits Shp2 phosphatase to Spry2 enhance its dephosphorylation, thereby...
Cockayne syndrome (CS) is an inherited disorder that involves photosensitivity, developmental defects, progressive degeneration and characteristics of premature aging. Evidence indicates primarily nuclear roles for the major CS proteins, CSA CSB, specifically in DNA repair RNA transcription. We reveal herein a complex regulation CSB targeting three consensus signals: NLS1 (aa467-481), which directs nucleolar localization cooperation with NoLS1 (aa302-341), NLS2 (aa1038-1055), seemingly...
ABSTRACT Age-related hearing loss (ARHL) is the most common sensory disability associated with human aging. Yet, there are no approved measures for preventing or treating this debilitating condition. With its slow progression, continuous and safe approaches critical ARHL treatment. Nicotinamide Riboside (NR), a NAD+ precursor, well tolerated even long-term use already shown effective in various disease models including Alzheimer’s Parkinson’s Disease. It has also been beneficial against...
Abstract Background Cockayne syndrome (CS) is a rare premature aging disease, most commonly caused by mutations of the genes encoding CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations have an average life expectancy 12 years. The proteins are involved in transcription DNA repair, with latter including transcription-coupled nucleotide excision repair (TC-NER). However, there also evidence for mitochondrial dysfunction CS, which likely...