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  • complexes
  • Most of the damage signals originated by the sensor complexes for the G 2 checkpoint are conducted to CDC25C, the activity of which is modulated by 14-3-3. (aacrjournals.org)
  • We are particularly interested in understanding how DNA damage is identified and resolved during DNA replication, when the genome is particularly vulnerable due to stalling of the replication fork at naturally arising and induced DNA lesions, structures or protein-DNA complexes. (stanford.edu)
  • As a result, most mitochondrial proteins are synthesized as precursors in the cytoplasm and imported across mitochondrial membranes by one or more translocase protein complexes (1). (cellsignal.com)
  • The central goal of our work is to develop novel multiscale computational protocols, which would allow integrative modeling of protein-nucleic acid complexes within the replisome. (nersc.gov)
  • We identified a mutation in tra1 , which encodes one of two homologs of transformation/transcription domain-associated protein (TRRAP), an ATM/R-related pseudokinase that scaffolds several histone acetyltransferase (HAT) complexes. (genetics.org)
  • DNA replication is a tightly regulated multistep process that requires the sequential action of several protein complexes that select DNA replication origins, recruit on these origins the DNA replication fork helicase that once activated, unwinds and duplicates the DNA. (g3journal.org)
  • This list also included high concentrations of proteins in the Mediator, spindle pole body/centrosome and actin cytoskeleton complexes. (biomedcentral.com)
  • Recombinantly expressed protein complexes of MUS81-EME1 (or -MMS4) versus native protein extract preparations differ especially in their ability to cleave an intact HJ, the central recombination intermediate. (plantphysiol.org)
  • chromatin
  • Here, starting from a comparative proteomic analysis of chromatin proteins in frog egg extracts, we demonstrated that CDCA7 is required for HELLS to associate with chromatin and exert nucleosome remodeling activity. (pnas.org)
  • pathways
  • The integrity of these checkpoint pathways is critical for the maintenance of genomic stability and cellular recovery from genotoxic damage. (aacrjournals.org)
  • New Pathways for Genome Stability/Human Disease: Recently, we performed a genome-wide siRNA screen to define the processes and proteins that protect cells from DNA damage, particularly during DNA replication. (stanford.edu)
  • The mismatch repair proteins function upstream in the DNA damage signaling pathways induced by the DNA methylating agent N -methyl- N ′ - nitro- N -nitrosoguanidine (MNNG). (pnas.org)
  • Because ssDNA is a common intermediate for many DNA repair pathways, this model explains nicely how ATR-dependent checkpoint pathways respond to different types of DNA damage. (pnas.org)
  • A pathway/functional analysis of celecoxib-affected transcripts, using Gene Ontology and Biocarta Pathways and exploring biological association networks, revealed that celecoxib modulates expression of numerous genes involved in a variety of cellular processes, including metabolism, cell proliferation, apoptotic signaling, cell cycle check points, lymphocyte activation, and signaling pathways. (aacrjournals.org)
  • The timing of Cdc2 activation is influenced by multiple checkpoint pathways that monitor the order and fidelity of cell cycle events, thus ensuring the readiness for chromosome segregation to proceed. (genetics.org)
  • The biological and (patho)physi- Department of Cell Cycle and Cancer, Institute of Cancer Biology, ological relevance of the checkpoint pathways is supported Danish Cancer Society, Strandboulevarden 49, DK-2100 by their evolutionary conservation , and it is evident from the consequences of checkpoint failure. (pharmapdf.com)
  • most checkpoint pathways operate only in cycling cells, which are at higher risk of fixing and propagating deleterious mutations [3- (pharmapdf.com)
  • the checkpoint pathways operating in various phases of the On the other hand, less is clearly more when it comes to mitotic cycles in mammalian somatic cells. (pharmapdf.com)
  • The latter are biochemical signalling These upstream elements of the checkpoint cascades are pathways that sense various types of structural defects in shared by diverse cell types and cell-cycle phases. (pharmapdf.com)
  • We also found a significant enrichment of proteins involved in telophase and cytokinesis, protein transport and endocytosis suggesting possible novel Tel1/Mec1 targets in these pathways. (biomedcentral.com)
  • Using a bioinformatic approach, we have generated a census of SCD-containing proteins that are involved not only in known DDR pathways but several other pathways under Tel1/Mec1 control suggesting new putative targets for these kinases. (biomedcentral.com)
  • MSH2
  • The ability of the MSH2/MSH6 heterodimer to bind a variety of modified DNA structure in vitro suggests a possibility that the MMR proteins may signal the DNA damage directly. (pnas.org)
  • multiple proteins
  • Among these targets, CHK1 seems to be the most suitable target for therapeutic G 2 abrogation to date, although an unexplored target such as 14-3-3 or the strategy of targeting multiple proteins at once may be of interest in the future. (aacrjournals.org)
  • mechanisms
  • It would be many years before the concept of the cell cycle checkpoint would be fully realized ( 3 ), not until the molecular mechanisms of cell cycle checkpoints were first elucidated in the late 1980s using yeasts, fungi, and the oocytes of amphibians. (aacrjournals.org)
  • When, concurrently, oncologists began examining the mechanisms of oncogenesis in higher eukaryotes using the same molecular biology techniques as their cell cycle counterparts, it was revealed that many cancer cells have defective G 1 checkpoint mechanisms and that cancer cells depend on G 2 checkpoint far more than normal cells ( 4 , 5 ). (aacrjournals.org)
  • The molecular mechanisms involved in checkpoint induction and maintenance are not known. (biologists.org)
  • Furthermore, the fundamental biological mechanisms and the dynamic protein associations in DNA synthesis and repair are conserved across bacterial, archaeal and eukaryotic organisms and govern many metabolic processes occurring in response to environmental stress as cells strive to regain homeostasis. (nersc.gov)
  • complex
  • DNA damage-inducible cell cycle checkpoints are complex signal transduction networks composed of cellular responses to genotoxic stresses. (aacrjournals.org)
  • One mechanism of DNA damage recognition has been elucidated recently, in which binding of replication protein A (RPA) to single-stranded DNA (ssDNA) results in recruitment of the ATR-interacting protein ATRIP to load the ATR/ATRIP complex to ssDNA, leading to activation of ATR ( 4 ). (pnas.org)
  • A complex network of proteins is activated on induction of DNA damage. (creativebiomart.net)
  • Following membrane fusion, the α-SNAP cytoplasmic adapter protein binds to the SNARE complex. (cellsignal.com)
  • The translocase of the outer mitochondrial membrane (TOM complex) facilitates the import of proteins through the outer mitochondrial membrane, while the complementary translocase of the inner membrane (TIM complex) is responsible for protein transport to the mitochondrial matrix. (cellsignal.com)
  • The TOM complex consists of the receptors Tom20, Tom22, and Tom70, and the channel-forming protein Tom40 (1). (cellsignal.com)
  • In a sequential process, recognition of the presequence by Tom20 is followed by tethering of the presequence to the Tom40 protein complex for efficient protein import (3). (cellsignal.com)
  • We have detected direct interactions between Ctf18-RFC and a number of the cohesion proteins including the four-subunit cohesin complex, Ctf7, Ctf4 and CHlR1. (mskcc.org)
  • Our present model of sister chromatid cohesion, shown in the figure below, is that there is a remodeling of the proteins at the replication fork that permits the fork to pass through sites at which the cohesin complex is deposited. (mskcc.org)
  • Pre-RC formation requires several loading factors including the hexameric Origin Recognition Complex ( ORC-1 -6), and Cdc6 and Cdt1 proteins. (g3journal.org)
  • We have previously described a G 1 -S checkpoint in fission yeast that delays formation of the prereplicative complex at chromosomal replication origins after exposure to UV light (UVC). (pnas.org)
  • DDB1 is part of an E3 ligase complex that includes the cullin proteins Cul4A and Cul4B. (aacrjournals.org)
  • Here, we show that damaged DNA-binding protein 1 (DDB1), a triple β propeller adapter protein, targets the Cul4 E3 ubiquitin ligase complex to Chk1. (aacrjournals.org)
  • Together, our study identifies a unique bipartite nucleosome remodeling complex where the functional remodeling activity is split between two proteins and thus delineates the defective pathway in ICF syndrome. (pnas.org)
  • MMS4 and MUS81 are in the same epistasis group for spore viability, consistent with biochemical data that show that the two proteins function in a complex. (genetics.org)
  • This protein complex has been shown to play an important role in DNA repair in human, yeasts, and Drosophila ( Drosophila melanogaster ), especially in dealing with stalled and collapsed replication forks and in the processing of recombination intermediates. (plantphysiol.org)
  • Pombe
  • A Rad1-deficient strain of S. pombe that fails to arrest normally at the G 2 /M boundary upon DNA damage (10) was used previously to screen a Xenopus laevis total ovary cDNA library for plasmids that conferred resistance to UV radiation. (aacrjournals.org)
  • genomic
  • The mismatch repair (MMR) proteins play key roles in postreplicational mispair correction that is essential for genomic stability ( 7 ). (pnas.org)
  • In wild-type cells, the frequency of genomic alterations of any type (point mutations, deletions, insertions, and chromosome rearrangements) is very low. (duke.edu)
  • The ability to preserve genomic integrity is a fundamental irreparable, checkpoints eliminate such potentially feature of life. (pharmapdf.com)
  • Such still largely ignorant of the impact of some of these variables mutations complement genetic recombination in providing on checkpoint control and execution, rapid advances have limited genomic plasticity necessary for the process of recently been made in understanding the molecular basis of evolution to select favourable traits for future generations. (pharmapdf.com)
  • arrest
  • Mechanistic elements of the first three tasks are emerging, yet themolecular basis of the recovery from checkpoint-mediated Addresses arrest remains unknown. (pharmapdf.com)
  • Chk1
  • Inhibition of histone deacetylases reverts the resistance to overexpressed chk1 + , suggesting this phenotype is due to a HAT activity, although expression of checkpoint and cell cycle genes is not greatly affected. (genetics.org)
  • Cells with mutant or deleted tra1 activate Chk1 normally and are checkpoint proficient. (genetics.org)
  • However, these cells are semi-wee even when overexpressing chk1 + and accumulate inactive Wee1 protein. (genetics.org)
  • Targeting the DDR through Chk1 inhibition, therefore, represents a novel therapeutic strategy to increase DNA-damaging chemotherapeutic drug induced tumor cell death in p53 pathway defective cancers [ 9 , 10 ] by abrogating the remaining intact checkpoint. (biomedcentral.com)
  • Here, we identify damaged DNA-binding protein 1 (DDB1) as a novel Chk1-interacting protein. (aacrjournals.org)
  • This study shows that Chk1 abundance is regulated by the Cul4A/DDB1 ubiquitin ligase during an unperturbed cell division cycle, in response to replicative stress and on heat shock protein 90 inhibition, and that deregulation of the Chk1/Cul4A/DDB1 pathway perturbs the ionizing radiation-induced G 2 checkpoint. (aacrjournals.org)
  • These include PP2A, which maintains Chk1 in a hypophosphorylated state in normal cycling cells ( 25 ), and PPM1D (Wip1), which dephosphorylates Chk1 during checkpoint recovery ( 26 ). (aacrjournals.org)
  • cytoplasmic
  • A digitonin option [150 μg/ml digitonin in 50 mM Hepes (pH 7.4)/100 Fasudil HCl mM KAc/2.5 mM MgAc] was added for 5 min as well as the lysate (cytoplasmic proteins) had been gathered (73). (desafioceroaedes.com)
  • yeast
  • Many checkpoint proteins have been identified through the investigation of yeast genetics. (aacrjournals.org)
  • Here, we explore the signal for activation of the Gcn2-dependent G 1 -S checkpoint in fission yeast. (pnas.org)
  • Here, we explore the signal for activation of the Gcn2-dependent G 1 -S checkpoint in fission yeast after exposure to UV light (UVC). (pnas.org)
  • Synapsis between homologous chromosomes in yeast begins when sister chromatids condense upon protein cores called axial elements (AEs), which are composed, at least in part, of three meiosis-specific proteins, Mek1p, Red1p, and Hop1p (reviewed by R oeder 1997 ). (genetics.org)
  • This new SCD definition was used in a custom bioinformatics pipeline to generate a census of SCD-containing proteins in both yeast and human. (biomedcentral.com)
  • In yeast, 436 proteins were identified, a significantly larger number of hits than were expected by chance. (biomedcentral.com)
  • In the human proteome, a wide range of similar proteins were identified, including homologs of some SCD-containing proteins found in yeast. (biomedcentral.com)
  • Molecular
  • The scope of celecoxib-modulated molecular alterations can best be studied by applying global approaches at the transcription and/or protein levels. (aacrjournals.org)
  • It is important to identify the molecular nature of the checkpoint trigger for at least two reasons: First, there is little information about such triggers for any checkpoint. (pnas.org)
  • ligase
  • The evolutionarily conserved Leucine Rich Repeat protein 1 ( LRR-1 ) is a substrate-recognition subunit of a CRL2 LRR-1 E3-ligase. (g3journal.org)
  • These results suggest that the CRL2 LRR-1 E3-ligase acts to modify or degrade factor(s) that would otherwise misregulate the replisome, eventually leading to the activation of the DNA replication checkpoint. (g3journal.org)
  • There are four distinct ligase proteins found in mammalian cells. (genetex.com)
  • Detection of human Ligase I protein in Raji whole cell lysate using GeneTex DNA Ligase I 10H5 monoclonal antibody GTX70141. (genetex.com)
  • A conserved physical and functional interaction between the cell cycle checkpoint clamp loader and DNA ligase I of eukaryotes. (genetex.com)
  • mutations
  • Therefore, checkpoints prevent accumulation of mutations and genome instability, which may lead to cancer development ( 2 ). (pnas.org)
  • Mutations in CDCA7, the SNF2 family protein HELLS (LSH), or the DNA methyltransferase DNMT3b cause immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome. (pnas.org)
  • Genes
  • Genetic studies, primarily in yeasts, have identified a number of genes essential for sister-chromatid cohesion which are categorized into three functional groups: structural proteins, deposition factors and establishment factors. (mskcc.org)
  • Altered expression of many of the genes by celecoxib was confirmed by quantitative PCR and at the protein level by Western blotting. (aacrjournals.org)
  • repair
  • Many tumor suppressors, such as p53, Chk2, and the breast cancer tumor suppressor BRCA1, are integral components of this network, which regulates cell cycle checkpoint activation and DNA repair. (pnas.org)
  • Alternatively, the checkpoint response can be activated indirectly through recognition of repair intermediates that are generated by MMR. (pnas.org)
  • MMS4
  • This work demonstrates that the mms4 sporulation defect is due to triggering of the meiotic recombination checkpoint. (genetics.org)
  • roles
  • We have identified new factors involved in these processes and ongoing projects relate to studying the roles of these factors and other known DDR proteins in these processes. (stanford.edu)
  • targets
  • DNA-PKcs primarily targets proteins involved in NHEJ and is recruited through Ku70/Ku80. (creativebiomart.net)
  • To identify all putative SCD-containing proteins, we analyzed the distribution of S/T-Q motifs within verified Tel1/Mec1 targets and arrived at a unifying SCD definition of at least 3 S/T-Q within a stretch of 50 residues. (biomedcentral.com)
  • functional
  • We were able to demonstrate that, after expression in Escherichia coli , each EME1 protein can assemble with the unique AtMUS81 to form a functional endonuclease. (plantphysiol.org)
  • response
  • Checkpoints delay the cell cycle in response to several forms of stress. (biologists.org)
  • Recently, the MMR system has also been implicated in S-phase checkpoint activation in response to low-dosage IR ( 15 ). (pnas.org)
  • Another important protein in the DDR, p53, is regulated by ATM and CHK2 in response to DSBs. (creativebiomart.net)
  • strong course="kwd-title" Keywords: Immunotherapy, immune-related undesirable occasions, melanoma, ipilimumab, imaging Intro Ipilimumab can be an immune system checkpoint inhibitor which blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) and augments T-cell immune system response against malignancy cells (1-6). (gonzalezgass.com)
  • Metabolic control of the Escherichia coli universal stress protein response through fructose-6-phosphate. (nih.gov)
  • To ensure faithful initiation wave of the G1 checkpoint (preceding the replication and transmission of the genome and to promote p53-mediated maintenance wave) and the transient survival, checkpoints fulfil at least four tasks: they rapidly intra-S-phase response. (pharmapdf.com)
  • But even among proliferating cells, the choice of checkpoint cascade(s) to be alarmed, and the outcome of such response, depends on many variables. (pharmapdf.com)