AnatomyOrganismsDiseasesChemicals and DrugsAnalytical, Diagnostic and Therapeutic Techniques and EquipmentPhenomena and ProcessesInformation ScienceHealth Care
Checkpoint Kinase 2DNA DamageCell Cycle ProteinsProtein-Serine-Threonine KinasesAtaxia Telangiectasia Mutated ProteinsDNA ReplicationProtein KinasesGenes, cdcHydroxyureaS PhaseCell CycleSaccharomyces cerevisiae ProteinsSchizosaccharomyces pombe ProteinsSchizosaccharomycesCell Cycle CheckpointsDNA, FungalG2 PhaseMitosisSaccharomyces cerevisiaeDNA-Binding ProteinsNuclear ProteinsPhosphorylationS Phase Cell Cycle CheckpointsFungal ProteinsUltraviolet Rayscdc25 PhosphatasesIntracellular Signaling Peptides and ProteinsDNA RepairMethyl MethanesulfonateTumor Suppressor ProteinsM Phase Cell Cycle CheckpointsMutationSpindle ApparatusCDC2 Protein KinaseGenomic InstabilitySignal TransductionNucleic Acid Synthesis InhibitorsReplication Protein CAphidicolinCyclin BG1 PhaseG2 Phase Cell Cycle CheckpointsDNA HelicasesKinetochoresReplication Protein AMolecular Sequence DataHeLa CellsNocodazoleChromatinGene Expression Regulation, FungalXenopus ProteinsModels, BiologicalGenes, FungalTumor Suppressor Protein p53AnaphaseDNA Breaks, Double-StrandedProtein BindingExodeoxyribonucleasesAmino Acid SequenceGamma RaysSecurinMad2 ProteinsCell LineDNASaccharomycetalesRadiation, IonizingCell NucleusBase SequenceCarrier ProteinsChromosome SegregationChromosomal Proteins, Non-HistoneGenome, FungalRecombination, GeneticHistonesRNA, Small InterferingCell DivisionCdc20 ProteinsEndonucleasesTelomereGene DeletionCell Line, TumorChromosomes, FungalAdaptor Proteins, Signal TransducingRepressor ProteinsPhenotypeDose-Response Relationship, RadiationEnzyme ActivationSequence Homology, Amino AcidMetaphaseProtein Structure, TertiaryCaffeineCyclin-Dependent Kinase Inhibitor p21Chromosomal InstabilityTemperatureCyclin-Dependent KinasesApoptosisImmunoblottingHCT116 CellsCyclin B1Transcription Factors
KinaseChk1ProteinsActivatesForksProteinChromatinGenesRecombinationProgressionStalled replication forkHomologousChromosomesMitosisInhibitorsLesionsCellularGenomic instabilityIntegrityBiological pathwaysRegulateMetabolicArrestEukaryoticRegulatesTranscriptionBreak induced replicationInstabilityMolecularTumorDistinctStabilityChromosomeCell cycleAntiapoptoticMechanismsSubunitSingle-strandedApoptosisKinasesTranscriptionalSynthesisCellsInducesStress
Kinase15
  • The focus of this study is the role of protein kinase Chk1 and the phosphatase Cdc25A in the DNA replication checkpoint. (vt.edu)
  • Inhibitor of checkpoint kinase CHK1 was identified as a top screen hit. (nature.com)
  • ATR kinase activates the S-phase checkpoint when replication forks stall at sites of DNA damage. (elsevierpure.com)
  • Together, our findings identify ATR as the kinase responsible for activating the FA pathway of DNA repair. (elsevierpure.com)
  • In addition, we investigated several cell cycle-related proteins and found that co-knockdown of hTopBP1 and hMYH significantly diminished cell cycle arrest due to compromised checkpoint kinase 1 (Chk1) activation. (biomedcentral.com)
  • The presence of replication stress activates the DNA damage response and downstream checkpoint proteins including ataxia telangiectasia and Rad3 related kinase (ATR), checkpoint kinase 1 (CHK1), and WEE1-like protein kinase (WEE1), which trigger cell cycle arrest while protecting and restoring stalled replication forks. (bmj.com)
  • Members of this kinase family have been shown to function in DNA repair and cell cycle checkpoint control following DNA damage. (bmj.com)
  • 8 , 9 The protein is a member of a novel family of large proteins, which show sequence homology to the catalytic domain of phosphatidylinositol 3 kinase, 3 and are implicated in cell cycle regulation, signal transduction, and the response to DNA damage. (bmj.com)
  • Inhibition of ribonucleotide reductase (RNR), the rate-limiting enzyme in the synthesis of deoxyribonucleotides, causes DNA replication stress and activates the ataxia telangiectasia and rad3-related protein (ATR)-checkpoint kinase 1 (CHK1) pathway. (figshare.com)
  • Similarly, activation of CDK2 by inhibition or knockdown of the WEE1 kinase also depletes RRM2 and causes DNA damage and apoptosis. (figshare.com)
  • ATM (ataxia-telangiectasia mutated) protein kinase is highly conserved in metazoan, and plays a critical role at DNA damage response, oxidative stress, metabolic stress, immunity, RNA biogenesis etc. (biomedcentral.com)
  • The ataxia-telangiectasia mutated (ATM) protein kinase is a member of the Phosphoinositide-3-Kinase (PI3K)-like Kinase (PIKK) family, and plays a master role to regulate DNA damage response (DDR), especially at double strand breaks (DSBs) repair, to maintain genome integrity [ 1 , 2 ]. (biomedcentral.com)
  • In response to DNA damage, the checkpoint kinase ATM phosphorylates and activates Chk2, which in turn directly phosphorylates and activates p53 tumor suppressor protein. (kegg.jp)
  • An inhibitor of ataxia telangiectasia and rad3-related (ATR) kinase, a DNA damage response kinase, with potential antineoplastic activity. (cancertreatmentsresearch.com)
  • Upon administration, berzosertib selectively binds to and inhibits ATR kinase activity and prevents ATR-mediated signaling in the ATR-checkpoint kinase 1 (Chk1) signaling pathway. (cancertreatmentsresearch.com)
Chk114
  • Chk1 is also transiently activated at the MBT in Xenopus laevis embryos, even when there is no block to DNA replication or damaged DNA. (vt.edu)
  • In order to understand the function and regulation of Chk1 in checkpoints, the features of the MBT that activate Chk1 must be identified. (vt.edu)
  • Embryos treated with aphidicolin, resulting in a halted replication fork and therefore a reduced DNA concentration, were tested for Chk1 activation and Cdc25A degradation. (vt.edu)
  • Investigating the mechanism of synthetic lethality, we reveal that CHK1 inhibition in IGF-1R depleted or inhibited cells further downregulated RRM2, reduced dNTP supply and profoundly delayed replication fork progression. (nature.com)
  • Exogenous RRM2 expression rescued hallmarks of replication stress induced by co-inhibiting IGF with CHK1 or WEE1, identifying RRM2 as a critical target of the functional IGF:CHK1 and IGF:WEE1 interactions. (nature.com)
  • hTopBP1 and hMYH were involved in ATR-mediated Chk1 activation, moreover, both of them were associated with ATR and hRad9 which known as checkpoint-involved proteins. (biomedcentral.com)
  • Our results suggested that hMYH is necessary for the accumulation of hTopBP1 to DNA damage lesion to induce the association of hTopBP1 with 9-1-1 and that the interaction between hMYH and hTopBP1 is essential for Chk1 activation. (biomedcentral.com)
  • Small molecule inhibitors designed to target the DNA damage sensors, such as inhibitors of ataxia telangiectasia-mutated (ATM), ATR, CHK1 and WEE1, impair smooth cell cycle modulation and disrupt efficient DNA repair, or a combination of the above, have demonstrated interesting monotherapy and combinatorial activity, including the potential to reverse drug resistance and have entered developmental pipelines. (bmj.com)
  • Here, we identified a feedback loop in Ewing sarcoma cells in which inhibition of the ATR-CHK1 pathway depletes RRM2, the small subunit of RNR, and exacerbates the DNA replication stress and DNA damage caused by RNR inhibitors. (figshare.com)
  • Overall, our results provide novel insight into the response to DNA replication stress, as well as a rationale for targeting the ATR, CHK1, and WEE1 pathways, in Ewing sarcoma tumors. (figshare.com)
  • Targeting the ATR, CHK1, and WEE1 kinases in Ewing sarcoma cells activates CDK2 and increases DNA replication stress by promoting the proteasome-mediated degradation of RRM2. (figshare.com)
  • All of these defects are associated with impaired activation of the ATR/CHK1 pathway. (nature.com)
  • Targeting ATR/CHK1 cell cycle checkpoint is a new approach in the post-PARPi era. (nih.gov)
  • ATR-Chk1-mediated protein degradation of Cdc25A protein phosphatase is also a mechanism conferring intra-S-phase checkpoint activation. (kegg.jp)
Proteins17
  • Studies in yeast and animals indicate that ASF1 proteins play important roles in various chromatin-based processes, including gene transcription, DNA replication and repair. (nih.gov)
  • The duplication of chromosomes and the regulation of their replication and repair requires dozens of proteins acting together to maintain the duplex DNA genome. (rockefeller.edu)
  • Activation of ATR phosphorylates a number of downstream proteins that coordinate the cell cycle checkpoint. (biomedcentral.com)
  • Whereas the different DNA repair pathways and the proteins they involve are know pretty well described, how they are regulated relative to each other in time and space remains to be deciphered. (cea.fr)
  • It seems now clear that posttranslational modification of both DNA repair and checkpoint proteins is of importance for the regulation of their activities but how these modifications are regulated and how they affect the activity of the proteins only begins to be described. (cea.fr)
  • Each origin is initiated by a combination of regulatory proteins that prepare the chromatin for replication before synthesis (S)-phase entry. (bmj.com)
  • Any obstacles encountered by cells in this process can lead to 'replicative stress' ( Figure 1 ), 1 which may be overcome by replicative stress response proteins, but deficiencies in this response result in accumulated errors in DNA replication and loss of genomic integrity, which lead to cell death. (bmj.com)
  • We are interested in understanding at the molecular level how recombination occurs and what roles are played by the many proteins involved in DNA recombination, repair and replication. (brandeis.edu)
  • We are interested in determining what are the specific biochemical roles played by the many proteins implicated in DNA recombination, repair and replication. (brandeis.edu)
  • We have identified the proteins necessary to carry out the initial steps in strand invasion and the beginning of new DNA synthesis, which is significantly different from the normal process of replication. (brandeis.edu)
  • 4 , 10 There is evidence to suggest that these proteins respond to DNA damage by phosphorylating one or more substrates, including p53, c-Abl, and replication protein A (RPA), to recruit proteins to regions of DNA repair and/or to activate radiation signal transduction pathways. (bmj.com)
  • Here we outline the current status of the viral evasion mechanism underlying the regulation of the cGAS-STING pathway, focusing on how post-transcriptional modifications, viral proteins, and non-coding RNAs involve innate immunity during viral infection, attempting to inspire new targets discovery and uncover potential clinical antiviral treatments. (frontiersin.org)
  • For instance, due to their genetic flexibility, viruses have developed various viral proteins and non-coding RNAs to interrupt several checkpoints of cGAS-STING. (frontiersin.org)
  • and the contribution of chromatin-modifying proteins to replication and repair. (usc.edu)
  • These compounds generally penetrate cell membranes, act on specific target proteins in cells, regulate intracellular signaling pathways, and cause some changes in cell phenotype. (chemscene.com)
  • The authors identified proteins associated with the yeast origin recognition complex (ORC), a set of proteins that binds chromosomal origins of DNA replication. (rupress.org)
  • Yph1p was also found in complex with a variety of other proteins, including those involved in ribosome biogenesis, cell cycle regulation, and checkpoint control. (rupress.org)
Activates3
  • Furthermore, the Atasf1ab-triggered replication fork stalling constitutively activates the DNA damage checkpoint and repair genes, including ATM, ATR, PARP1 and PARP2 as well as several genes of the homologous recombination (HR) pathway but not genes of the non-homologous end joining (NHEJ) pathway. (nih.gov)
  • This may suggest that caspase-2 activates a non-canonical replication checkpoint to facilitate DNA repair. (nature.com)
  • Akbari MR, Malekzadeh R, Nasrollahzadeh D, activates EGFR pathway signaling in the lung. (who.int)
Forks8
  • His lab studies how the replisome interacts with DNA repair and cell cycle checkpoint machinery, how initiation of replication is directed by nucleosomes, and how replication forks perform nucleosome inheritance, the process by which nucleosomes (the fundamental structural unit of chromosomal DNA) are passed down from parental to daughter DNA during replication. (rockefeller.edu)
  • During ATR signaling in response to DNA damage, Rad17 forms a complex with 9-1-1 and loads onto stalled replication forks [ 4 - 9 ]. (biomedcentral.com)
  • Replication of DNA is initiated at multiple sites along the genome, known as replication origins, which form bidirectional replication forks. (bmj.com)
  • Chromatin assembly and the establishment of sister chromatid cohesion are intimately connected to the progression of DNA replication forks. (cell-stress.com)
  • We propose a model where caspase-2 regulates the cell cycle and protects DNA replication forks to prevent DNA damage accrual in a pathway distinct from its apoptotic role. (nature.com)
  • In our paper published in Oncogene [6], we show that caspase-2 plays an essential role in regulating normal cell division by protecting DNA replication forks from replication stress. (nature.com)
  • We show that caspase-2 protects cells from a range of S-phase-related defects, including delayed exit from S-phase, increased stalled replication forks, increased new replication origins, and decreased repair of S-phase-associated chromosomal aberrations [6]. (nature.com)
  • Homologous recombination is the main mechanism to repair DNA lesions that block replication forks and fill ssDNA gaps left behind the fork [11]. (nature.com)
Protein16
  • this protein prevents efficient repair of DNA damage, leading to the accumulation of mutations in other genes. (diff.org)
  • This event also causes phosphorylation of the Fanconi anemia (FA) protein FANCI, triggering its monoubiquitination of the key DNA repair factor FANCD2 by the FA core E3 ligase complex, thereby promoting this central pathway of DNA repair which permits replication to be restarted. (elsevierpure.com)
  • Human DNA topoisomerase II-binding protein 1 (hTopBP1) plays an important role in DNA replication and the DNA damage checkpoint pathway. (biomedcentral.com)
  • The ataxia telangiectasia and Rad3-related protein (ATR) signaling cascade is an important pathway involved in the checkpoint control mechanism [ 3 ]. (biomedcentral.com)
  • Human DNA topoisomerase II-binding protein 1 (TopBP1) and its orthologs play important roles in DNA replication and checkpoint control [ 1 ]. (biomedcentral.com)
  • RAD9A is highly similar to Schizosaccharomyces pombe rad9, a cell cycle checkpoint protein required for cell cycle arrest and DNA damage repair in response to DNA damage. (avivasysbio.com)
  • This protein is found to possess 3' to 5' exonuclease activity, which may contribute to its role in sensing and repairing DNA damage. (avivasysbio.com)
  • It forms a checkpoint protein complex with RAD1 and HUS1. (avivasysbio.com)
  • This complex is recruited by checkpoint protein RAD17 to the sites of DNA damage, which is thought to be important for triggering the checkpoint-signaling cascade. (avivasysbio.com)
  • Resection is accompanied by the binding of replication protein A (RPA) to the 3' single-stranded overhangs, which helps recruiting the checkpoint complexes. (cea.fr)
  • RPA, replication protein A. (rupress.org)
  • This protective effect of preaccumulated p53 was mediated, at least in part, by the increased expression of CDKN1A/p21, subsequent down-regulation of BRCA1, and impaired JNK activation accompanied by decreased association of replication protein A with chromatin. (rupress.org)
  • 1). A protein interaction map (PIM) was built, and the main modules within the network were identified and focused on the different pathways and BP analyses. (genominfo.org)
  • A protein found in DNA replication complexes is also essential for ribosome biosynthesis, according to new results from Yi-Chieh Du and Bruce Stillman (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY). (rupress.org)
  • 2) functions of differentially expressed genes in atm mutated flies, regardless of protein-coding genes or non-coding RNAs, are closely related with metabolic process, immune response, DNA damage response or oxidative stress. (biomedcentral.com)
  • Dr. Maity obtained his Ph.D. in Cellular and Molecular Biology from the Life Science and Biotechnology department at Jadavpur University, India in 2017, where he studied the DNA damage repair protein WRN and autophagy. (nih.gov)
Chromatin7
  • Taken together, our study establishes crucial roles for the AtASF1A and AtASF1B genes in chromatin replication, maintenance of genome integrity and cell proliferation during plant development. (nih.gov)
  • Additionally, the checkpoint kinases modify the chromatin surrounding DNA damages through phosphorylation of the H2A histone (H2AX in mammals). (cea.fr)
  • Here we examined the genetic interaction between the heterotrimeric chromatin assembly factor-1 (CAF-1), a central component of chromatin assembly during replication, and the core replisome component Ctf4. (cell-stress.com)
  • We present evidence that CAF-1 affects cohesin association to chromatin in a DNA-damage-dependent manner and is essential to maintain cohesion in the absence of CTF4 . (cell-stress.com)
  • Finally, our data indicate that the CAF-1-dependent pathway required for cohesion is functionally distinct from the Rtt101-Mms1-Mms22 pathway which functions in replicated chromatin assembly. (cell-stress.com)
  • Collectively, our results suggest that the deposition by CAF-1 of newly-synthesized H3-H4 histones during DNA replication creates a chromatin environment that favors sister chromatid cohesion and maintains genome integrity. (cell-stress.com)
  • 2) How does chromatin modification at sites of DNA damage regulate DNA repair and transcription? (mdanderson.org)
Genes9
  • Selective up-regulation of expression of a subset of genes, including those involved in S-phase checkpoints and the CYCB1;1 gene at the Gā‚‚-to-M transition, was observed in Atasf1ab. (nih.gov)
  • In spite of the activation of repair genes, an increased level of DNA damage was detected in Atasf1ab, suggesting that defects in the mutant largely exceed the available capacity of the repair machinery. (nih.gov)
  • Random set analysis was used to identify biological pathways enriched for genes differentially regulated in tumors (compared with 59 samples of normal mucosa). (biomedcentral.com)
  • The cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway is a critical defender to sense various pathogens and trigger innate immunity of mammalian cells. (frontiersin.org)
  • Defects in processes that modulate cell division, such as mutations in genes that participate in DNA repair, uncorrected errors during replication, or broken, missing, rearranged, or extra chromosomes, are the principal drivers of genomic instability. (foundmyfitness.com)
  • The most responsible genes and pathways involved in the pathology of this disorder have not been fully understood. (genominfo.org)
  • We aimed to identify differentially expressed genes (DEGs), the most critical hub genes, transcription factors, signaling pathways, and biological processes (BPs) associated with the pathogenesis of primary SGC. (genominfo.org)
  • Despite many types of investigation that have been performed, the most critical genes and signaling pathways taking part in the etiology of the disease have not been fully demonstrated [ 5 ]. (genominfo.org)
  • Her laboratory takes multidisciplinary approach to identify important players in the DNA damage response and define the roles of these genes in maintaining genomic stability and tumor suppression. (mdanderson.org)
Recombination5
  • Studies the molecular mechanisms of DNA replication, recombination, and repair. (rockefeller.edu)
  • Change in localisation depends on the checkpoint kinases Tel1ATM and Mec1ATR and has a positive effect on spontaneous recombination. (cea.fr)
  • Both homologous recombination, in which the ends of the broken DNA seek out intact templates with the same sequence, and nonhomologous end-joining pathways are found in Saccharomyces as they are in humans. (brandeis.edu)
  • This "in vivo biochemistry" approach has enabled us to demonstrate that there are in fact several independent, competing pathways of homologous recombination, each with its own genetic requirements. (brandeis.edu)
  • In the absence of CTF4 , CAF-1 is essential for viability in cells experiencing replication problems, in cells lacking functional S-phase checkpoint or functional spindle checkpoint, and in cells lacking DNA repair pathways involving homologous recombination. (cell-stress.com)
Progression5
  • Furthermore, poorer prognosis in cancer patients who display a glycolytic phenotype characterized by metabolic alterations, such as obesity and diabetes, is now well established, providing another link between metabolic pathways and cancer progression. (springer.com)
  • This allowed us to distinguish between pathways whose dysregulation is probably necessary throughout tumorigenesis and those whose involvement specifically drives progression from one stage to the next. (biomedcentral.com)
  • In the presence of errors or damage during DNA replication, cell cycle checkpoint nodes and repair machinery work in concert to retard cell cycle progression until sufficient repair has been achieved. (bmj.com)
  • [3] Cellular checkpoints and DNA damage-response pathways help preserve genomic stability and cell-cycle progression, but these processes decline with aging. (foundmyfitness.com)
  • Mitotic cell cycle progression is accomplished through a reproducible sequence of events, DNA replication (S phase) and mitosis (M phase) separated temporally by gaps known as G1 and G2 phases. (kegg.jp)
Stalled replication fork2
  • Another function of Pol IV is to perform translesion synthesis at the stalled replication fork like, for example, bypassing N2-deoxyguanine adducts at a faster rate than transversing undamaged DNA. (wikipedia.org)
  • Emam A, Wu X, Xu S, Wang L, Liu S, Wang B . Stalled replication fork protection limits cGAS-STING and P-body-dependent innate immune signalling. (mdanderson.org)
Homologous2
  • HR comprises different pathways: gene conversion (GC) that accurately repair the lesion by copying the homologous sequence, single strand annealing (SSA) or break induced replication (BIR) that can both lead to loss of genetic information. (cea.fr)
  • Histone 2A has several variants, including H2AX, which plays essential roles in DNA repair, specifically non-homologous end joining, a pathway that repairs double-strand breaks. (foundmyfitness.com)
Chromosomes1
Mitosis3
  • In Xenopus laevis, early embryonic development consists of twelve rapid cleavage cycles between DNA replication (S) and mitosis (M) without checkpoints or gap phases. (vt.edu)
  • The checkpoint original model represents the activity of Cdc25 phosphatase on the mitosis promoting factor (MPF) that leads the cell into mitosis. (vt.edu)
  • In addition cells have evolved a damage-sensing checkpoint system whereby the cells delay entry into mitosis until the break has been repaired. (brandeis.edu)
Inhibitors5
  • Immunotherapy mainly includes immune checkpoint inhibitors (ICIs), such as inhibitors of PD-1 (programmed cell death 1)/programmed cell death ligand 1 (PD-L1). (nature.com)
  • Immune checkpoint inhibitors are effective in the treatment of some hepatocellular carcinomas (HCCs), but these tumors do not always respond to inhibitors of programmed cell death 1 (PDCD1, also called PD1). (stanford.edu)
  • Background Checkpoint inhibitors have not been effective for prostate cancer as single agents. (bmj.com)
  • Data from other trials suggest there may be improved activity in men with DNA damage repair (DDR) mutations treated with checkpoint inhibitors. (bmj.com)
  • Cyclin-CDK inhibitors (CKIs), such as p16Ink4a, p15Ink4b, p27Kip1, and p21Cip1, are involved in the negative regulation of CDK activities, thus providing a pathway through which the cell cycle is negatively regulated. (kegg.jp)
Lesions1
  • This creates a checkpoint, stops replication, and allows time to repair DNA lesions via the appropriate repair pathway. (wikipedia.org)
Cellular6
  • These alterations can take the form of epigenetic modifications, point mutations, translocations, amplifications or deletions and modify gene functions in ways that deregulate cellular signalling pathways leading to the cancer phenotype. (bmj.com)
  • 9 The exact number and nature of genetic alterations and deregulated signalling pathways required for tumorigenesis remains an issue of debate, 10 although it is now clear that central nervous system (CNS) carcinogenesis requires multiple disruptions to the normal cellular circuitry. (bmj.com)
  • UV irradiation represents a major challenge to genomic integrity throughout the evolution of terrestrial organisms, resulting in the development of specific mechanisms that govern the cellular response to UV-induced DNA damage. (rupress.org)
  • Cellular senescence , the process by which damaged cells terminate normal growth and reproduction cycles to prevent injured cells from proliferating. (foundmyfitness.com)
  • Hypoxia, due to the lack of oxygen (O2) as the electron recipient, causes inefficient electron transfer through the electron transport chain at the mitochondria leading to accumulation of reactive oxygen species (ROS) which could create irreversible cellular damages. (stanford.edu)
  • Though Stillman admits the link between DNA replication and ribosome biosynthesis is speculative, he adds that it makes sense, as proliferation requires the replication of both the genome and the cellular machineries. (rupress.org)
Genomic instability2
Integrity4
  • One goal of this work is to understand the developmental role and regulation of checkpoint signaling pathways due to its monitoring of DNA integrity within the cell. (vt.edu)
  • Maintaining genomic integrity is of utmost importance to eukaryotic cells, which have evolved sophisticated mechanisms to ensure speed, accuracy, and an adequate pool of nucleotide and replication factors as well as high-fidelity repair pathways to correct errors occurring during DNA replication. (bmj.com)
  • Unscheduled transcription and alternative pre-mRNA splicing induced by DNA damage signify great threat to genome integrity. (biomedcentral.com)
  • Her research is focused on understanding how cells respond to DNA damage and safeguard the integrity of the genome. (mdanderson.org)
Biological pathways1
  • Mathematical modeling is the translating of biological pathways into mathematical equations that can simulate interactions without performing laboratory experiments. (vt.edu)
Regulate2
  • During the cell cycle, there are two main checkpoints that regulate entrance into S and M phases. (vt.edu)
  • ATM and PIKK members influence DNA damage induced transcription through post-translational modification of RNA polymerase II (RNA pol II), transcription elongation factors, and multiple transcription factors, to regulate RNA-dependent DNA damage repair [ 17 , 18 ]. (biomedcentral.com)
Metabolic2
  • S transition in the cell cycle, upregulated expression of tumor-promoting microenvironmental factors, and profound dysregulation of metabolic pathways (e.g., increased aerobic glycolysis, downregulation of pathways that metabolize drugs and xenobiotics). (biomedcentral.com)
  • Therefore, a metabolic shift from mitochondrial respiration to the glycolytic pathway occurs during OB differentiation. (nih.gov)
Arrest4
  • When unreplicated or damaged DNA is present, cell cycle checkpoint pathways cause cell cycle arrest by inhibiting cyclin-dependent kinases (Cdks). (vt.edu)
  • In contrast, while caspase-2-deficiency led to an increased proportion of S-phase cells and a progressive decrease in the proportion of G1-phase cells following treatment with arresting concentrations of the DNA damaging agent camptothecin and increased DNA damage following S-phase arrest, overexpression of Bcl-X L did not change the cell cycle profiles or the amount of DNA damage. (nature.com)
  • While other groups have demonstrated non-apoptotic roles for caspase-2 in DNA repair, cell cycle arrest [2], this is the first demonstration that these roles are regulated by a distinct pathway to apoptosis. (nature.com)
  • Eukaryotic cells respond to DNA damage by activating signaling pathways that promote cell cycle arrest and DNA repair. (kegg.jp)
Eukaryotic3
  • These studies can be expected to provide new insights into eukaryotic replication, repair, and epigenetic inheritance. (rockefeller.edu)
  • Tunability of DNA polymerase stability during eukaryotic DNA replication. (rockefeller.edu)
  • Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. (innatedb.com)
Regulates2
  • If caspase-2 regulates cell division through the same pathway, it would be expected to phenocopy the cell cycle results of caspase-2 null cells. (nature.com)
  • Consistent with our evidence that caspase-2 regulates a replication checkpoint, the chromosomal aberrations detected in caspase-2-deficient cells are not repaired before metaphase. (nature.com)
Transcription1
Break induced replication1
  • This is the process we have studied most intensively, but we are also interested in an alternative process known as break-induced replication (BIR), where only one end of a chromosome break locates a template sequence and assembles a complete replication fork and can copy sequences to the end of a chromosome, producing a nonreciprocal translocation. (brandeis.edu)
Instability1
  • The Forsburg lab uses a mixture of classical genetics, molecular biology, and state-of-the-art microscopy to investigate how defects in replication contribute to genome instability during normal cell growth and during the differentiation process of meiosis. (usc.edu)
Molecular3
  • Intriguingly, many of these mechanisms utilize the same molecular pathways that are altered through calorie and/or carbohydrate restriction. (springer.com)
  • We used a molecular pathway-based approach to analyze transcriptomic profiles of 59 colorectal tumors representing early and late preinvasive stages and the invasive stage of tumorigenesis. (biomedcentral.com)
  • Thus, hTopBP1 constitutes an important part of the ATR signaling pathway and acts as a molecular bridge that associates the independently recruited 9-1-1 and ATR-ATRIP complexes, thereby leading to checkpoint activation [ 4 ]. (biomedcentral.com)
Tumor4
  • Of the 880 canonical pathways we investigated, 112 displayed significant tumor-related upregulation or downregulation at one or more stages of tumorigenesis. (biomedcentral.com)
  • Caspase-2 is most well-known for initiating the intrinsic apoptosis pathway [1] and as a tumor suppressor [2]. (nature.com)
  • In addition to participation in proteasome function, this subunit may also participate in the TNF signalling pathway since it interacts with the tumor necrosis factor type 1 receptor. (innatedb.com)
  • This prevents DNA damage checkpoint activation, disrupts DNA damage repair, and induces tumor cell apoptosis. (cancertreatmentsresearch.com)
Distinct3
  • Even as the nature of the exact cell in which Merkel cell carcinoma oncogenesis occurs is controversial, there is strong support for the notion that Merkel cell carcinoma results from of one of two distinct pathways. (medscape.com)
  • This indicates a role distinct from caspase-2's reported role in inducing apoptosis to remove damaged or aneuploid cells [7][8]. (nature.com)
  • Thus, caspase-2 activation during replication stress engages a pathway distinct from that engaged by cytokinesis failure. (nature.com)
Stability2
Chromosome1
  • Unrepaired or incorrectly repaired DNA damage may lead to loss of heterozygosity, mutations, deletions, genomic rearrangements and chromosome loss. (cea.fr)
Cell cycle7
  • Another means of characterizing the unreplicated DNA checkpoint is through the use of mathematical modeling of the checkpoint-signaling cascade of the cell cycle. (vt.edu)
  • The early preinvasive stage was characterized by cell-cycle checkpoint activation triggered by DNA replication stress and dramatic downregulation of basic transmembrane signaling processes that maintain epithelial/stromal homeostasis in the normal mucosa. (biomedcentral.com)
  • Therefore, we suggest that the interaction between hMYH and hTopBP1 is crucial for activation of the ATR-mediated cell cycle checkpoint. (biomedcentral.com)
  • In general, NHEJ is the preferred pathway in the G1 phase of the cell cycle, while HR is favored in S and G2 phases. (cea.fr)
  • Strategies that increase replicative stress while lowering cell cycle checkpoint thresholds may allow unrepaired DNA damage to be inappropriately carried forward in replicating cells, leading to mitotic catastrophe and cell death. (bmj.com)
  • The most significant pathways and BPs that were deregulated in the primary disease condition were associated with the cell cycle and fibroblast proliferation procedures. (genominfo.org)
  • Consistent with this, we noted a caspase-2-dependent slowdown of the cell cycle following mild replication stress. (nature.com)
Antiapoptotic1
  • Intrinsic factors include chronically activated proliferative, invasive, and antiapoptotic signaling pathways. (springer.com)
Mechanisms1
  • [1] The mechanisms that drive inflammaging and the pathological conditions that arise because of it are bidirectional and involve multiple physiological processes and pathways, many of which directly or indirectly intersect with some of the hallmarks described below. (foundmyfitness.com)
Subunit1
  • We recently reported that genetic or pharmacological inhibition of insulin-like growth factor receptor (IGF-1R) slows DNA replication and induces replication stress by downregulating the regulatory subunit RRM2 of ribonucleotide reductase, perturbing deoxynucleotide triphosphate (dNTP) supply. (nature.com)
Single-stranded2
  • Replication fork activation is enabled by a single-stranded DNA gate in CMG helicase. (rockefeller.edu)
  • These effects resulted in significant accumulation of unreplicated single-stranded DNA and increased cell death, indicative of replication catastrophe. (nature.com)
Apoptosis1
Kinases1
  • In this study, we show that Tip60 is required for the early DNA damage response (DDR) to UV, including the phosphorylation of histone 2AX, c-Jun N-terminal kinases (JNKs), and ataxia telangiectasia-related substrates. (rupress.org)
Transcriptional1
  • p53 and its transcriptional targets play an important role in both G1 and G2 checkpoints. (kegg.jp)
Synthesis1
  • DNA polymerase IV can catalyze translesion synthesis across a variety of DNA damages including 8-oxoguanine, a major oxidative damage with high mutagenic potential. (wikipedia.org)
Cells7
  • Cells lacking dinB gene have a higher rate of mutagenesis caused by DNA damaging agents. (wikipedia.org)
  • The team employs strategies such as super resolution microscopy to observe individual replisomes in real time during DNA replication in living cells, and cryo-electron microscopy of DNA-replisome and other replisome-associated complexes. (rockefeller.edu)
  • cells in recognizing damaged or broken DNA strands. (diff.org)
  • many of the body's cells from correctly repairing damaged DNA. (diff.org)
  • RT-induced damage to cancer cells leads to different outcomes, such as survival, senescence, or death. (nature.com)
  • Specifically, the concepts of tumour heterogeneity, oncogene addiction, non-oncogene addiction, tumour initiating cells, tumour microenvironment, non-coding sequences and DNA damage response will be reviewed. (bmj.com)
  • We find that CAF-1 deficient cells as well as cells affected in newly-synthesized H3-H4 histones deposition during DNA replication exhibit a severe negative growth with ctf4 āˆ† mutant. (cell-stress.com)
Induces1
Stress2