To cause genomic instability particularly at chromosome loci that are intrinsically difficult to replicate because of the complexity of secondary structures or
DNA replication is tightly regulated, but paradoxically there is reported to be an excess of MCM DNA replication proteins over the number of replication origins. Here, we show that MCM levels in primary human T cells are induced during the G(0)--,G(1) transition and are not in excess in proliferating cells. The level of induction is critical as we show that a 50% reduction leads to increased centromere separation, premature chromatid separation (PCS) and gross chromosomal abnormalities typical of genomic instability syndromes. We investigated the mechanisms involved and show that a reduction in MCM levels causes dose-dependent DNA damage involving activation of ATR & ATM and Chk1 & Chk2. There is increased DNA mis-repair by non-homologous end joining (NHEJ) and both NHEJ and homologous recombination are necessary for Mcm7-depleted cells to progress to metaphase. Therefore, a simple reduction in MCM loading onto DNA, which occurs in cancers as a result of aberrant cell cycle control, is ...
R‐loops, formed by co‐transcriptional DNA-RNA hybrids and a displaced DNA single strand (ssDNA), fulfill certain positive regulatory roles but are also a source of genomic instability. One key cellular mechanism to prevent R‐loop accumulation centers on the conserved THO/TREX complex, an RNA‐binding factor involved in transcription elongation and RNA export that contributes to messenger ribonucleoprotein (mRNP) assembly, but whose precise function is still unclear. To understand how THO restrains harmful R‐loops, we searched for new THO‐interacting factors. We found that human THO interacts with the Sin3A histone deacetylase complex to suppress co‐transcriptional R‐loops, DNA damage, and replication impairment. Functional analyses show that histone hypo‐acetylation prevents accumulation of harmful R‐loops and RNA‐mediated genomic instability. Diminished histone deacetylase activity in THO‐ and Sin3A‐depleted cell lines correlates with increased R‐loop formation, ...
R‐loops, formed by co‐transcriptional DNA-RNA hybrids and a displaced DNA single strand (ssDNA), fulfill certain positive regulatory roles but are also a source of genomic instability. One key cellular mechanism to prevent R‐loop accumulation centers on the conserved THO/TREX complex, an RNA‐binding factor involved in transcription elongation and RNA export that contributes to messenger ribonucleoprotein (mRNP) assembly, but whose precise function is still unclear. To understand how THO restrains harmful R‐loops, we searched for new THO‐interacting factors. We found that human THO interacts with the Sin3A histone deacetylase complex to suppress co‐transcriptional R‐loops, DNA damage, and replication impairment. Functional analyses show that histone hypo‐acetylation prevents accumulation of harmful R‐loops and RNA‐mediated genomic instability. Diminished histone deacetylase activity in THO‐ and Sin3A‐depleted cell lines correlates with increased R‐loop formation, ...
Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation. In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation. The phosphatidylinositol 3-kinase δ (PI3Kδ) pathway regulates AID by suppressing its expression in B cells. Drugs for leukaemia or lymphoma therapy such as idelalisib, duvelisib and ibrutinib block PI3Kδ activity directly or indirectly, potentially affecting AID expression and, consequently, genomic stability in B cells. Here we show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhanced the expression of AID and increased ...
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Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy. The sources of genome instability have only recently begun to be elucidated. A high frequency of externally caused DNA damage can be one source of genome instability since DNA damages can cause inaccurate translesion synthesis past the damages or errors in repair, leading to mutation. Another source of genome instability may be epigenetic or mutational reductions in expression of DNA repair genes. Because endogenous (metabolically-caused) DNA damage is very frequent, ...
Large-scale genomic studies have demonstrated that approximately 50% of high-grade serous ovarian cancers (HGSOCs) harbor genetic and epigenetic alterations in homologous recombination repair (HRR) pathway genes. The most commonly altered HRR genes are BRCA1 and BRCA2, followed by other Fanconi Anemia genes. Loss of HRR causes genomic instability, hyperdependence on alternative DNA repair mechanisms, and enhanced sensitivity to PARP-inhibitors (PARPi) through the mechanism of synthetic lethality. PARP inhibitor resistance has emerged as a vexing clinical problem for the treatment of BRCA1/2 deficient tumors. The most prevalent mechanism of PARPi resistance is secondary events that cancel the original HRR alteration and restore HRR proficiency. PARPi resistance also develops without restoration of HRR proficiency through enhanced replication fork (RF) stabilization. We have recently made the surprising observation that BRCA2-deficient tumor cells can stabilize their replication forks and become ...
Tumor-suppressor recruits help to overcome a barrier and fix cancer-causing defects. Like a mechanic popping the hood of a car to get at a faulty engine, a tumor-suppressing protein allows cellular repair mechanisms to pounce on damaged DNA by overcoming a barrier to DNA access.. Reporting online at Nature Cell Biology this week, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center shows that BRIT1 connects with another protein complex to relax DNAs tight packaging at the site of the damage.. "Relaxing this barrier allows two different DNA repair pathways greater access to the damage, preventing flawed DNA from being passed on as the cell divides, which causes genomic instability leading to cancer," said senior author Shiaw-Yih Lin, Ph.D., assistant professor in M. D. Andersons Department of Systems Biology.. BRIT1 is under-expressed in human ovarian, breast and prostate cancer cell lines. Lin and colleagues previously showed that the protein plays a key ...
DNA-protein crosslinks (DPCs) are under-investigated DNA lesions caused by the covalent attachment of proteins to DNA. DPCs are induced by various endogenous chemicals like aldehydes or by chemotherapeutic drugs. Little is known about how cells repair DPCs and thus acquire resistance to DPC-induced chemotherapy. However, the persistence of DPCs causes genomic instability and cancer. We recently discovered a human syndrome (Ruijs-Aalfs or SPARTAN syndrome) related to the defective DPC repair pathway.
Despite its benefits in cancer treatment, ionising radiation (IR) can induce a series of adverse acute and/or long term effects. Studies on A-bomb survivors and radiotherapy patients have shown that acute whole-body exposure results in an increased risk for radiation-induced Acute Myeloid Leukaemia (r-AML), a bone marrow (BM) malignancy; whereas local-radiotherapy patients run the risk of developing acute and/or long term normal tissue reactions. Irradiated BM cells manifest persistent radiation-induced genomic instability. BM is one of the most susceptible tissues to radiation-induced cancer and one of the most radiosensitive tissues, which proposes a link between cancer susceptibility, genomic instability and radiosensitivity. The exact mechanism by which exposure of BM cells to IR leads to malignant transformation is still unclear, but the non-targeted nature of radiation-induced damage and genomic instability could suggest that an epigenetic mechanism is also involved; and DNA methylation is ...
Genomic instability plays a key role in driving cancer development. It is already found in precancerous lesions and allows the acquisition of additional cancerous features. A major source of genomic instability in early stages of tumorigenesis is DNA replication stress. Normally, origin licensing and activation, as well as replication fork progression, are tightly regulated to allow faithful duplication of the genome. Aberrant origin usage and/or perturbed replication fork progression leads to DNA damage and genomic instability. Oncogene activation is an endogenous source of replication stress, disrupting replication regulation and inducing DNA damage. Oncogene-induced replication stress and its role in cancer development have been studied comprehensively, however its molecular basis is still unclear. Here, we review the current understanding of replication regulation, its potential disruption and how oncogenes perturb the replication and induce DNA damage leading to genomic instability in cancer.
Dr. Changs research program focuses on telomeres,repetitive DNA sequences at the ends of chromosomes critically important for the maintenance of genome stability. Perturbation of telomere length results in telomere dysfunction, leading to increased genomic instability that can promote early aging and cancer development. Dr. Changs laboratory was the first togenerate a faithful mouse model of Werner Syndrome (WS). This rare disease strikes individuals in their 30s and is marked by the development of aging phenotypes and early onset of cancer.. Dr. Chang found that when WRN deficiency is coupled withtelomere dysfunction, the combination increases genomic instability, pre-matureaging and increased tumorigenesis. In addition, his findings conclusively demonstrate that telomere status plays an important role in the development of premature aging pathologies observed in WS patients. With this mouse model, Dr. Changs laboratory has also identified common genetic pathways that unify aging and cancer ...
Dr. Changs research program focuses on telomeres,repetitive DNA sequences at the ends of chromosomes critically important for the maintenance of genome stability. Perturbation of telomere length results in telomere dysfunction, leading to increased genomic instability that can promote early aging and cancer development. Dr. Changs laboratory was the first togenerate a faithful mouse model of Werner Syndrome (WS). This rare disease strikes individuals in their 30s and is marked by the development of aging phenotypes and early onset of cancer.. Dr. Chang found that when WRN deficiency is coupled withtelomere dysfunction, the combination increases genomic instability, pre-matureaging and increased tumorigenesis. In addition, his findings conclusively demonstrate that telomere status plays an important role in the development of premature aging pathologies observed in WS patients. With this mouse model, Dr. Changs laboratory has also identified common genetic pathways that unify aging and cancer ...
Inverted repeats have been found to occur in both prokaryotic and eukaryotic genomes. Usually they are short and some have important functions in various biological processes. However, long inverted repeats are rare and can cause genome instability. Analyses of C. elegans genome identified long, nearly-perfect inverted repeat sequences involving both divergently and convergently oriented homologous gene pairs and complete intergenic sequences. Comparisons with the orthologous regions from the genomes of C. briggsae and C. remanei show that the inverted repeat structures are often far more conserved than the sequences. This observation implies that there is an active mechanism for maintaining the inverted repeat nature of the sequences.
Shepard JL, Amatruda JF, Stern HM, Subramanian A, Finkelstein D, Ziai J, Finley KR, Pfaff KL, Hersey C, Zhou Y, Barut B, Freedman M, Lee C, Spitsbergen J, Neuberg D, Weber G, Golub TR, Glickman JN, Kutok JL, Aster JC, Zon LI (2005) A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility. Proc Natl Acad Sci USA 102: 13194-13199 ...
Hannes Alfvén. Plasma instabilities are not well-known to the general public, or among astronomers. They refer to distortions that occur when plasmas are generated and confined. They are often confused with phenomena observed in fluid interactions: Kelvin-Helmholtz instabilities, or Rayleigh-Taylor instabilities, for instance.. Since plasmas are conventional matter with a small percentage of ionized particles, they do not conform to kinetic energy principles, alone. Rather, matter in the plasma state is strongly influenced by electromagnetism, and does not obey any other force, including gravity, except peripherally. Many types of instability are observed in plasma: diocotron instabilities, kink instabilities, edge instabilities (that make fusion reactors impossible to control), sausage instabilities (deformations in plasma flow), reactive instabilities, etc.. A principle tenet of Electric Universe theory is that various plasmas (mostly hydrogen ions and helium nuclei) comprise 99.99% of the ...
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An experiment is performed to assess the prevalence of instability in univariate and bivariate macroeconomic time series relations and to ascertain whether various adaptive forecasting techniques successfully handle any such instability. Formal tests for instability and out-of-sample forecasts from sixteen different models are computed using a sample of 76 representative U.S. monthly postwar macroeconomic time series, constituting 5700 bivariate forecasting relations. The tests indicate widespread instability in univariate and bivariate autoregressive models. However, adaptive forecasting models, in particular time varying parameter models, have limited success in exploiting this instability to improve upon fixed-parameter or recursive autoregressive forecasts. ...
Transcription and replication are the two major DNA metabolic processes in cells. Both machineries involve large protein complexes progressing along the DNA at high speed and for long distances. Importantly, a large body of evidence suggests that encounters between DNA and RNA polymerases can induce replication fork arrest, DNA breaks, recombination intermediates and mutations, thereby causing genetic instability1-3. However, their role how they affect the underlying chromatin structure and cause epigenetic instability is largely unexplored ...
Correspondence re: Zimonjic et al. 2001. Derivation of human tumor cells in vitro without widespread genomic instability. Cancer Res no. 61 (24):8838-44. Submitted to Cancer Research 8/19/2002, r... Read It Review It ...
Author: Perry Nickelston. Title: Five Hidden Signs of Instability. Summary: If you work with patients long enough, you come to realize a few in-the-trenches facts. Here are five biggies that require constant consideration...
Trouvez tous les livres de Schmeidler, Lacey - Instability, Liquidity and World Money. Sur eurolivre.fr,vous pouvez commander des livres anciens et neufs.COMPARER ET acheter IMMÉDIATEMENT au meilleur prix. 9783845404103
that instability can occur even after the full establishment of the primary flow. Chandrasekhars method is used in the analysis and the relationship between the stability parameter and the wave number of the disturbance for neutral stability is obtained."--Page 1 ...
Estrogen-mediated high reactive oxygen species (ROS) tolerance plays an important role in driving carcinogenesis. ROS overproduction acts as the significant effector to increase genomic instability...
History Gene amplification is a frequent manifestation of genomic instability that plays a role in tumour progression and development of drug resistance. formation of micronuclei or nuclear buds which correlated with the removal of and increased sensitivity to MTX. These Indoximod findings indicate for the first time that NHEJ plays a specific role in DM formation and that increased MTX sensitivity of DM-containing cells depleted of DNA-PKcs results from removal. Conversely in HSR-containing cells we found no significant switch in the expression of NHEJ proteins. Depletion of DNA-PKcs experienced no effect on amplification and resulted in only a modest increase in sensitivity to MTX. Interestingly both DM-containing and HSR-containing cells exhibited decreased proliferation upon DNA-PKcs depletion. Conclusions We demonstrate a novel specific role for NHEJ in the formation of DMs but not HSRs in MTX-resistant cells and that NHEJ may be Indoximod targeted for the treatment of MTX-resistant colon ...
A summary of the 2nd NO-Age International symposium: Genomic instability in human brain Amund Hov[1], Ruben Gudmundsrud[1], Brian C. Gilmour[1], Hilde L. Nilsen[1][2], Jon Storm-Mathisen[1][3], Linda H. Bergersen[1][4][5], Evandro F. Fang[1][2][1] The Norwegian Centre on Healthy Ageing (NO-Age), Norway[2] Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway[3] Amino Acid…
Avgustinova A, Symeonidi A, Castellanos A, Urdiroz-Urricelqui U, Solé-Boldo L, Martín M, Pérez-Rodríguez I, Prats N, Lehner B, Supek F, Benitah SA ...
wrong paths and the others of minutes and new runs. After refining actions and conflicting iBooks to send the Flash browser, CREATIONS and positions ve displayed in web. The new pursuit of the it is parsing process permissions with Adobe AIR, leading political Tunes, and developing with selected time permissions.
Structures of thin films bonded on thick substrates are abundant in biological systems and engineering applications. Mismatch strains due to expansion of the films or shrinkage of the substrates can induce various modes of surface instabilities such as wrinkling, creasing, period doubling, folding, ridging, and delamination. In many cases, the film-substrate structures are not flat but curved. While it is known that the surface instabilities can be controlled by film-substrate mechanical properties, adhesion and mismatch strain, effects of the structures curvature on multiple modes of instabilities have not been well understood. In this paper, we provide a systematic study on the formation of multimodal surface instabilities on film-substrate tubular structures with different curvatures through combined theoretical analysis and numerical simulation. We first introduce a method to quantitatively categorize various instability patterns by analyzing their wave frequencies using fast Fourier ...
Persistent genetic instability in cancer cells induced by non-DNA-damaging stress exposures.s profile, publications, research topics, and co-authors
InterPro provides functional analysis of proteins by classifying them into families and predicting domains and important sites. We combine protein signatures from a number of member databases into a single searchable resource, capitalising on their individual strengths to produce a powerful integrated database and diagnostic tool.
Instabilities in polymer processing limit production rates and may influence to some degree the optical or mechanical properties of the final product. One prominent example is the fountain flow instability, which takes place during the mold filling stage of an injection molding process. Old car bumpers which show light and dark lines are a famous example of an injection molded part in which such an instability occurred.
High dose ionizing radiation (IR) is a well-known risk factor for breast cancer but the health effects after low-dose (LD, |10 cGy) exposures remain highly uncertain. We explored a systems approach that compared LD-induced chromosome damage and transcriptional responses in strains of mice with genetic differences in their sensitivity to radiation-induced mammary cancer (BALB/c and C57BL/6) for the purpose of identifying mechanisms of mammary cancer susceptibility. Unirradiated mammary and blood tissues of these strains differed significantly in baseline expressions of DNA repair, tumor suppressor, and stress response genes. LD exposures of 7.5 cGy (weekly for 4 weeks) did not induce detectable genomic instability in either strain. However, the mammary glands of the sensitive strain but not the resistant strain showed early transcriptional responses involving: (a) diminished immune response, (b) increased cellular stress, (c) altered TGFβ-signaling, and (d) inappropriate expression of developmental
Some aging theories such as the Hallmarks of aging implicate DNA damage as one of the primary driving processes of aging contributing to genomic instability.
Video created by Johns Hopkins University for the course Introduction to the Biology of Cancer. Now, well turn our attention to the genetics of cancer, variation and mutation, two-hit hypothesis, and genomic instability. 2000+ courses from ...
The Jackson Laboratory, which has had an NCI-designated Cancer Center since 1983, has research programs studying cancer initiation and progression, cancer cell genomic architecture, cancer genome instability and repair, and more.
For the function of evaluating the combustion instability of Ariane strong booster equally experimental and numerical operate was carried out in the f
Eros Di Giorgio, Harikrishnareddy Paluvai, Emiliano Dalla, Liliana Ranzino, Alessandra Renzini, Viviana Moresi, Valentina Cutano, Raffaella Picco, Claudio Brancolini
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is negative, one expects curvature instabilities of the membrane and, in turn, these instabilities generate a pattern of domains that differ both in composition and in local curvature. Scaling arguments motivate the study of the family of singular perturbed energies ...
P.M. Lushnikov, Dva mekhanizma vozbuzhdeniya poverkhnostnykh voln: neustoichivost Kelvina-Gelmgoltsa i neustoichivost Mailsa, Izv. AN. Fizika Atmosfery i Okeana, 34, 413-421 (1998) [P.M. Lushnikov, Two mechanisms of surface waves generation: Kelvin-Helmholtz instability and Miles instability, Izvestiya, Atmospheric and Oceanic Physics (1998)]. ...
Strategies the pa- tient has used to reduce risk for infection are identified.1994; Zwangersschap and Shine, 1992; Mishima et al.
2019 marks a year of instability and uncertainty reflected in the field of potential best picture nominees, from Parasite to Joker.
You hindquarters look at with hormonal instability by managing your every day accentuate level, feeding a ... lasting, that feels eff it or non is.
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In the process of cancer initiation and progression, various types of cellular stress such as inflammation cause genomic mutations including single nucleotide polymorphisms and copy number variations in oncogenes and tumor suppressors, as well as epigenetic changes, in multiple stages via pre-neoplastic lesions. Since most of the data of human cancer samples were obtained retrospectively from fully-developed tumor tissues, it is hard to predict how and when the mutations were induced, and how alterations to gene expression, genomic mutations and epigenetic modifications lead to the development of these tumors.. By using in vitro carcinogenic system, we aim to clarify how the transcription regulatory network is shifted from normal to cancer mode, and the dynamics of chromatin structure in the carcinogenesis process. By introducing oncogenes and chemically-induced carcinogenic animal models, we have performed spatiotemporal analysis of transcription regulatory networks and signal pathways in the ...
Purpose: The role and clinical implication of the transmembrane protein with EGF and two follistatin motifs 2 (TMEFF2) in gastric cancer is poorly understood.. Experimental Design: Gene expression profile analyses were performed and Gene Set Enrichment Analysis (GSEA) was used to explore its gene signatures. AGS and MKN45 cells were transfected with TMEFF2 or control plasmids and analyzed for gene expression patterns, proliferation, and apoptosis. TMEFF2 expression was knocked down with shRNAs, and the effects on genome stability were assessed. Interactions between TMEFF2 and SHP-1 were determined by mass spectrometry and immunoprecipitation assays.. Results: Integrated analysis revealed that TMEFF2 expression was significantly decreased in gastric cancer cases and its expression was negatively correlated with the poor pathologic stage, large tumor size, and poor prognosis. GSEA in The Cancer Genome Atlas (TCGA) and Jilin datasets revealed that cell proliferation, apoptosis, and DNA ...
Changes in the genome that allow uncontrolled cell proliferation or cell immortality are responsible for cancer. It is believed that the major changes in the genome that lead to cancer arise from mutations in tumor suppressor genes. In 1997, Kinzler and Bert Vogelstein grouped these cancer susceptibility genes into two classes: "caretakers" and "gatekeepers". In 2004, a third classification of tumor suppressor genes was proposed by Franziska Michor, Yoh Iwasa, and Martin Nowak; "landscaper" genes. Caretaker genes encode products that stabilize the genome. Fundamentally, mutations in caretaker genes lead to genomic instability. Tumor cells arise from two distinct classes of genomic instability: mutational instability arising from changes in the nucleotide sequence of DNA and chromosomal instability arising from improper rearrangement of chromosomes. In contrast to caretaker genes, gatekeeper genes encode gene products that act to prevent growth of potential cancer cells and prevent accumulation ...
Dr. Murray Junop and his team of researchers, located in the biochemistry department at Western University, are studying how preventing genetic instability can be used in combination with other types of cancer treatment to provide more effective methods of cancer therapy. Read more in The Londoner.