A5042695459- Telomeres, Telomerase, and Senescence
- DNA Repair Mechanisms
- Protein Structure and Dynamics
- Enzyme Structure and Function
- RNA and protein synthesis mechanisms
- NF-κB Signaling Pathways
- Advanced biosensing and bioanalysis techniques
- RNA Interference and Gene Delivery
- PARP inhibition in cancer therapy
- Cancer-related Molecular Pathways
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Retinoids in leukemia and cellular processes
- Epigenetics and DNA Methylation
- Autophagy in Disease and Therapy
- interferon and immune responses
- Cell death mechanisms and regulation
- X-ray Diffraction in Crystallography
- Ubiquitin and proteasome pathways
- Genetics, Aging, and Longevity in Model Organisms
- Crystallization and Solubility Studies
- Immune cells in cancer
- Polyomavirus and related diseases
- Advanced Glycation End Products research
- Protein Interaction Studies and Fluorescence Analysis
- Nutrition and Health in Aging
Centre Hospitalier de l’Université de Montréal
2015-2025
Université de Montréal
2016-2025
Lawrence Berkeley National Laboratory
2004-2019
Institute for Research in Immunology and Cancer
2018
Block Center
2015
Buck Institute for Research on Aging
2007-2014
Hôpital Notre-Dame
2000-2013
Virginia Commonwealth University
2012
Center for Drug Evaluation and Research
2012
University of California, Berkeley
2012
Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays provide a quantitative assessment factors secreted senescent cells. show that human cells induced senesce stress secrete myriad associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days only after DNA damage sufficient...
The ability to express or deplete proteins in living cells is crucial for the study of biological processes. Viral vectors are often useful deliver DNA constructs that difficult transfect by other methods. Lentiviruses have additional advantage being able integrate into genomes non-dividing mammalian cells. However, existing viral expression systems generally require different vector backbones cDNA, small hairpin RNA (shRNA) microRNA (miRNA) and provide limited drug selection markers....
Most of the nuclear genome warm-blooded vertebrates is a mosaic very long (> > 200 kilobases) DNA segments, isochores ; these are fairly homogeneous in base composition and belong to small number major classes distinguished by differences guanine-cytosine (GC) content. The families molecules derived from such can be separated used study distribution any sequence which probed. This approach has revealed (i) that genes, integrated viral sequences, interspersed repeats highly nonuniform...
DNA damage can induce a tumor suppressive response termed cellular senescence. Damaged senescent cells permanently arrest growth, secrete inflammatory cytokines and other proteins harbor persistent nuclear foci that contain (DDR) proteins. To understand how differ from transient mark repairable lesions, we identify sequential events differentiate foci, which term 'DNA segments with chromatin alterations reinforcing senescence' (DNA-SCARS). Unlike DNA-SCARS associate PML bodies, lack the...
Cellular senescence suppresses cancer by preventing the proliferation of cells that experience potentially oncogenic stimuli. Senescent often express p16(INK4a), a cyclin-dependent kinase inhibitor, tumor suppressor, and biomarker aging, which renders growth arrest irreversible. also acquire complex phenotype includes secretion many cytokines, factors, proteases, termed senescence-associated secretory (SASP). The SASP is proposed to underlie age-related pathologies, including, ironically,...
Senescence is a cellular program that irreversibly arrests the proliferation of damaged cells and induces secretion inflammatory mediators IL- 6 IL-8 which are part larger senescence associated secretory phenotype (SASP). We screened quiescent senescent human fibroblasts for differentially expressed microRNAS (miRNAs) found miRNAs 146a 146b (miR-146a/b) were significantly elevated during senescence. suggest delayed miR-146a/b induction might be compensatory response to restrain inflammation....
Cellular senescence irreversibly arrests cell proliferation in response to oncogenic stimuli. Human cells develop a senescence-associated secretory phenotype (SASP), which increases the secretion of cytokines and other factors that alter behavior neighboring cells. We show here "senescent" mouse fibroblasts, arrested growth after repeated passage under standard culture conditions (20% oxygen), do not express human-like SASP, differ from similarly cultured human respects. However, when...
Cellular senescence irreversibly arrests proliferation in response to potentially oncogenic stress. Senescent cells also secrete inflammatory cytokines such as IL-6, which promote age-associated inflammation and pathology. HMGB1 (high mobility group box 1) modulates gene expression the nucleus, but certain immune an extracellular Alarmin signal tissue damage. We show that nuclear relocalized milieu senescent human mouse culture vivo. In contrast cytokine secretion, redistribution required...
Senescence is a tumor suppression mechanism defined by stable proliferation arrest. Here we demonstrate that the known synthetic lethal interaction between poly(ADP-ribose) polymerase 1 inhibitors (PARPi) and DNA repair triggers p53-independent ovarian cancer cell senescence senescence-associated phenotypic hallmarks including DNA-SCARS, inflammatory secretome, Bcl-XL-mediated apoptosis resistance, restriction via Chk2 p21 (CDKN1A). The concept of as irreversible remains controversial here...
Abstract The subunit interfaces of 122 homodimers known three‐dimensional structure are analyzed and dissected into sets surface patches by clustering atoms at the interface; 70 single‐patch, others have up to six patches, often contributed different structural domains. average interface buries 1,940 Å 2 each monomer, contains one or two burying 600–1,600 , is 65% nonpolar includes 18 hydrogen bonds. However, range size hydrophobicity wide among interfaces. Each has a core made residues with...
Abstract Packing contacts are crystal artifacts, yet they make use of the same forces that govern specific recognition in protein‐protein complexes and oligomeric proteins. They provide examples a nonspecific interaction which can be compared to biologically relevant ones. We evaluate number size pairwise interfaces 152 forms where asymmetric unit contains monomeric protein. In those have no element 2‐fold symmetry, we find molecules form 8 10 interfaces. The total area surface buried on...
Abstract We present an analysis of the water molecules immobilized at protein–protein interfaces 115 homodimeric proteins and 46 complexes, compare them with 173 large crystal packing representing nonspecific interactions. With average 15 waters per 1000 Å 2 interface area, are more hydrated than specific homodimers which have 10–11 , reflecting hydrophilic composition interfaces. Very different patterns hydration observed: Water may form a ring around that remain “dry,” or they permeate...
Summary Cellular senescence suppresses cancer by arresting the proliferation of cells at risk for malignant transformation. Recently, senescent were shown to secrete numerous cytokines, growth factors, and proteases that can alter tissue microenvironment may promote age‐related pathology. To identify small molecules suppress senescence‐associated secretory phenotype (SASP), we developed a screening protocol using normal human fibroblasts library compounds are approved use. Among promising...
Summary Exposure to IR has been shown induce the formation of senescence markers, a phenotype that coincides with lifelong delayed repair and regeneration irradiated tissues. We hypothesized IR‐induced markers could persist long‐term in vivo , possibly contributing permanent reduction tissue functionality. Here, we show mouse tissues exposed sublethal dose display persistent (up 45 weeks, maximum time analyzed) DNA damage foci increased p16 INK4a expression, two hallmarks cellular aging....
Aging may be determined by a genetic program and/or the accumulation rate of molecular damages. Reactive oxygen species (ROS) generated mitochondrial metabolism have been postulated to central source damages and imbalance between levels intracellular ROS antioxidant defenses is characteristic aging brain. How modifies free radicals concentrations increases risk develop most neurodegenerative diseases poorly understood, however. Here we show that Polycomb group oncogene Bmi1 required in...
Exposure of MCF-7 breast tumor cells or HCT-116 colon carcinoma to clinically relevant concentrations doxorubicin (Adriamycin; Farmitalia Research Laboratories, Milan, Italy) camptothecin results in both autophagy and senescence. To determine whether is required for chemotherapy-induced senescence, reactive oxygen generation induced by Adriamycin was suppressed <i>N</i>-acetyl cysteine glutathione, the induction ataxia telangiectasia mutated, p53, p21 modulated pharmacologically and/or...
Cellular senescence is a tumor-suppressive mechanism that can paradoxically contribute to aging pathologies. Despite evidence of immune clearance in mouse models, it not known how senescent cells (SnCs) persist and accumulate with age or tumors individuals. Here, we identify cooperative mechanisms orchestrate the immunoevasion persistence normal cancer human SnCs through extracellular targeting natural killer receptor signaling. Damaged avoided recognition MMP-dependent shedding NKG2D...
Sustained macroautophagy/autophagy favors the differentiation of fibroblasts into myofibroblasts. Cellular senescence, another means responding to long-term cellular stress, has also been linked myofibroblast and fibrosis. Here, we evaluate relationship between senescence in context sustained autophagy. We analyzed markers cell cycle arrest/senescence vitro, where autophagy was triggered by serum starvation (SS). Autophagic expressed biomarkers CDKN1A/p21 CDKN2A/p16 exhibited increased...