Kinase response to dna damage and replication. Medical search. Frequent questions

and the contribution of chromatin-modifying proteins to replication and repair. (usc.edu)
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)
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)
DNA-repair enzyme inhibitors attack the cancer cell proteins (enzymes) that normally repair damage to DNA. (lls.org)
Histone deacetylase inhibitors attack cancer cells by targeting the proteins that support DNA in the cell nucleus. (lls.org)
PI3K (phospho inositide 3 kinases) inhibitors are a group of closely related kinase proteins. (lls.org)
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)
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)
J-H Lee et al also have provided the first evidence showing that PIG3 is closely associated with the induction and maintenance of the phosphorylation of H2AX and some other DDR proteins after DNA damage induced by NCS ( 8 ). (ijbs.com)
Eukaryotic cells activate an evolutionarily conserved set of proteins that rapidly induce cell cycle arrest to prevent replication or segregation of damaged DNA before repair is completed. (wustl.edu)
The laboratory of Dr. Hasan studies the interplay between anti-apoptotic proteins and cyclin dependent kinases and how this interplay can serve as a potential therapeutic target in Acute Myeloid Leukemia (AML). (actrec.gov.in)
In response to DNA harm phosphatidylinositol (PI)-3 kinase-related kinases ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3-related) are primarily activated and eventually phosphorylate several proteins including Rad17 as well as the Chk1 kinase. (biobender.com)
The ATR-Chk1 axis is certainly central towards the DDR and crucial for preserving genome integrity and they're regarded as DNA harm sensor proteins in cells. (biobender.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)
Thus, the dephosphorylation of target proteins by PP4 is equally important in DDR as much as phosphorylation by kinases. (molcells.org)
The protein PCNA, which clamps onto DNA, also helps cells resolve replication stress by serving as a platform for repair proteins. (rupress.org)
Researchers have discovered numerous proteins that are involved in replication stress, and Hoffmann et al. (rupress.org)
When the researchers used mass spectrometry to identify the proteins that accumulate at damaged DNA undergoing replication in Xenopus egg extracts, they found one that hadn't turned up in previous studies: the E3 ubiquitin ligase TRAIP. (rupress.org)
To find out how it gets into position at the sites of DNA damage, the researchers removed different sections of TRAIP and tested the truncated proteins' ability to home in on the lesions. (rupress.org)
Recent breakthroughs have uncovered more and more DNA replication licensing machinery proteins (ORC, Cdc6, Cdt1, geminin, etc.) functioning in other cell cycle events, including centrosome replication, mitotic events, transcription and so on. (intechopen.com)
To do so, they coupled findings from 238 DNA-protein-binding experiments performed by the ENCODE project - a massive, multiyear international effort to identify the functional elements of the human genome - with a laboratory-based technique to identify binding patterns among the proteins themselves. (pharmaceuticalintelligence.com)
Proteins control gene expression by either binding to specific regions of DNA, or by interacting with other DNA-bound proteins to modulate their function. (pharmaceuticalintelligence.com)
Previously, researchers could only analyze two to three proteins and DNA sequences at a time, and were unable to see the true complexities of the interactions among proteins and DNA that occur in living cells. (pharmaceuticalintelligence.com)
The ENCODE, for the Encyclopedia of DNA Elements , project was a five-year collaboration of more than 440 scientists in 32 labs around the world to reveal the complex interplay among regulatory regions, proteins and RNA molecules that governs when and how genes are expressed. (pharmaceuticalintelligence.com)
In this way, they were able to tell which proteins interacted directly with one another, and which were seen together because their preferred DNA binding sites were adjoining. (pharmaceuticalintelligence.com)
PARP-1 binding to sites of DNA damage results in activation of its catalytic activity and generation of chains of poly (ADP-ribosyl)ated polymers, which serve as docking sites for recruitment of DNA repair proteins. (survivornet.com)
In addition, chronic diagnostic test for follow-up of patients cy and for biochemical determination inflammation associated with the infec- with H. pylori gastritis and were able of tissue COX-2 activity using COX tion leads to damage in proteins, the to predict the risk of development of Activity Assay Kit (Cayman Chemical production of reactive oxygen species stomach cancer. (who.int)

We investigated the ability of the ATR inhibitor, AZD6738, to prevent the gemcitabine-induced intra-S-phase checkpoint activation and evaluated the antitumor potential of this combination in vitro and in vivo In PDAC cell lines, AZD6738 inhibited gemcitabine-induced Chk1 activation, prevented cell-cycle arrest, and restrained RRM2 accumulation, leading to the strong induction of replication stress markers only with the combination. (nih.gov)
His laboratory also contributed to understanding how replication origins are regulated by checkpoint kinases in response to DNA damage. (royalsociety.org)
Members of this kinase family have been shown to function in DNA repair and cell cycle checkpoint control following DNA damage. (bmj.com)
We demonstrate that lack of FAS1 activity results in the activation of an ATAXIA TELANGIECTASIA MUTATED (ATM)- and SUPPRESSOR OF GAMMA-RESPONSE 1 (SOG1)-mediated G2/M-arrest that renders the ATR and WEE1 checkpoint regulators redundant. (muni.cz)
Knocking out SOG1 in the fast weel background restores replication stress sensitivity, demonstrating that SOG1 is an important secondary checkpoint regulator in plants that fail to activate the intra-S-phase checkpoint. (muni.cz)
Our results reveal the specific and essential functions of Cdk2 inhibitory phosphorylation in the successful execution of the replication stress checkpoint response and in maintaining genome integrity. (cancerrealitycheck.com)
The persistent fork progression in HU-treated Cdk2AF/AF cells indicates that Cdk2 inhibitory phosphorylation is required for normal Corynoxeine execution of the S-phase checkpoint induced by replication stress. (cancerrealitycheck.com)
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)
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)
Late origin firing is blocked in response to DNA damage via Dbf4 phosphorylation by the Rad53 checkpoint kinase. (bvsalud.org)
In response to ionizing radiation (IR), the cell cycle checkpoint kinase, Chk2 (hCds1), is phosphorylated and activated in an ataxia telangiectasia mutated (ATM)-dependent manner. (wustl.edu)
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)
The studies on checkpoint control have identified a mechanism by which entry into mitosis is regulated in response to incomplete DNA replication and DNA damage and the identification of a potential target for therapeutic intervention. (actrec.gov.in)
Background: The product of this gene is an essential upstream regulator of checkpoint kinase 1 and triggers a checkpoint arrest of the cell cycle in response to replicative stress or DNA damage. (idhinhibitor.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)
SRA737 is a potent, highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key regulator of cell cycle progression and the DNA Damage Response (DDR). (salesandmarketingnetwork.com)
Human DNA topoisomerase II-binding protein 1 (hTopBP1) plays an important role in DNA replication and the DNA damage checkpoint pathway. (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)

We show that TTFields robustly activates PARP- and ATR-mediated DNA repair (including PARylation and CHK1 phosphorylation, respectively), whilst combining TTFields with PARP1 or ATR inhibitor treatment leads to significantly reduced clonogenic survival. (nature.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)
PIG3 knockdown led to an abnormal DNA damage response, including decreased IR-induced phosphorylation of H2AX, Chk1, Chk2 and Kap-1 as well as a prolonged G2-M arrest and aberrant mitotic progression. (ijbs.com)
Hence the ATR-Chk1 axis may be used to check environmental substances that could induce DNA harm. (biobender.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)
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)

The MCM complex is the DNA helicase that opens the helix at the replication origin and unwinds the two strands as the replication forks travel along the DNA. (wikipedia.org)
Replication of DNA is initiated at multiple sites along the genome, known as replication origins, which form bidirectional replication forks. (bmj.com)
This proceeds to phosphorylating a number of protein that regulate the DNA-damage response (DDR) including cell routine arrest stabilization of stalled replication forks and DNA fix [32]. (biobender.com)
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 stress refers to the various impediments that can slow or stall replication forks. (rupress.org)
Because stalled forks can lead to DNA double-strand breaks and genome instability, cells take a series of measures to clear the obstacles and restart replication ( 2 ). (rupress.org)
The long stretches of single-stranded DNA at stalled forks attract the protein RPA ( 3 ). (rupress.org)
WS have been classified is a member of the RecQ family of DNA helicases implicated in the resolution of DNA structures leading to the stall of replication forks. (medscape.com)

Here we show that the ATM protein kinase directly phosphorylates T68 within the SQ/TQ-rich domain of Chk2 in vitro and that T68 is phosphorylated in vivo in response to IR in an ATM-dependent manner. (wustl.edu)
Ataxia-telangiectasia-related (ATR) protein kinase is central to the deoxyribonucleic acid (DNA) damage response and homologous recombination, activating a series of phosphorylation cascades, culminating in cell cycle arrest to allow time for deoxyribonucleic acid (DNA) repair. (survivornet.com)

However, recent data suggest that TTFields may also attenuate DNA damage repair and replication fork dynamics, providing a potential platform for therapeutic combinations incorporating standard-of-care treatments and targeted DNA damage response inhibitors (DDRi). (nature.com)
JAK inhibitors block the enzymes JAK1, JAK2, JAK3 and tyrosine kinase 2, which play a role in the cell-signaling process that leads to the inflammatory and immune responses seen in certain diseases. (lls.org)
Cdk2AF cells also exhibited strikingly abnormal responses to replication stress accumulated irreparable DNA damage and permanently exited the cell cycle after transient exposure to S-phase inhibitors. (cancerrealitycheck.com)
Genome instability activates stress kinases, implying that kinase inhibitors may form the basis of antiaging therapies for individuals with WS. (medscape.com)

We conclude that Cdk2 inhibitory phosphorylation is required for normal replication dynamics in asynchronous and arrested cells. (cancerrealitycheck.com)
Discussion Our study reveals essential roles for Cdk2 T14/Y15 phosphorylation in maintaining genome integrity and in preventing DNA damage when S phase is stalled. (cancerrealitycheck.com)
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)
Compared to HL60 cells, the tyrosine phosphorylation level in K562 cells was markedly increased, suggesting that the increase in tyrosine phosphorylation is due to BCR ABL tyrosine kinase activity, which was confirmed by the expression of BCR ABL shown only in K562 cells. (rafinhibitors.com)
During S phase, helicase activation requires MCM phosphorylation by Dbf4-dependent kinase (DDK), comprising Cdc7 and Dbf4. (bvsalud.org)
Truncation of the Dbf4 docking domain abrogates DH phosphorylation, yet Cdc7 kinase activity is unaffected. (bvsalud.org)
Our results explain the structural basis and regulation of the selective phosphorylation of DNA-loaded MCM DHs, which supports bidirectional replication. (bvsalud.org)
In these same conditions, VE-821 induced DNA damage and consequently increased Ataxia Telangiectasia Mutated-mediated phosphorylation of H2AX and KAP1. (ox.ac.uk)

Here, the authors, through a comprehensive proteomics analysis, identify ATR as a potential therapeutic target of neuroblastoma and demonstrate the efficacy of the ATR inhibitor BAY1895344 in combination with the ALK tyrosine kinase inhibitor lorlatinib. (ugent.be)

Moreover we found that Cdk2AF/AF cells replicated more DNA during HU arrest than Cdk2+/+ cells as shown by the increased track lengths in HU-treated Cdk2AF/AF cells compared with untreated cells (Fig. 5 and for details on statistical analysis). (cancerrealitycheck.com)
Eukaryotic cells respond to DNA damage by activating signaling pathways that promote cell cycle arrest and DNA repair. (kegg.jp)
RESULTS: VE-821 was shown to inhibit ATR-mediated signalling in response to replication arrest induced by severe hypoxia. (ox.ac.uk)
Protein phosphatase 4 (PP4) is a crucial protein complex that plays an important role in DNA damage response (DDR), including DNA repair, cell cycle arrest and apoptosis. (molcells.org)
To prevent these detrimental consequences, eukaryotic cells have evolved an elaborate and complex system, so called DNA damage response (DDR) comprising of DNA DSB repair, cell cycle arrest, apoptosis, and transcriptional regulation ( Jackson and Bartek, 2009 ). (molcells.org)

Then I thought, there must be a sensory pathway that recognizes the DNA damage that's going on in the cell," says Elledge. (the-scientist.com)
Skin fibroblasts in WS patients demonstrate characteristics of cells in conditions of stress with slow growth rates, an elongated cell cycle, and an altered morphology that suggests stress-induced premature senescence transduced in part by the p38α MAP kinase signaling pathway. (medscape.com)

B-Raf is a member of the Raf kinase family of growth signal transduction protein kinases. (rafinhibitors.com)

DNA re-replication (or simply rereplication) is an undesirable and possibly fatal occurrence in eukaryotic cells in which the genome is replicated more than once per cell cycle. (wikipedia.org)
To prevent rereplication, eukaryotic cells have evolved multiple, overlapping mechanisms to inhibit chromosomal DNA from being partially or fully rereplicated in a given cell cycle. (wikipedia.org)
His first experimental results contained a serendipitous artifact that laid the foundation for a scientific career studying how eukaryotic cells deal with damage to their DNA. (the-scientist.com)
Elledge's idea that eukaryotic cells sense the progress of DNA replication and transform that information into a DNA-damage response was new. (the-scientist.com)
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)
DNA replication occurs once and only once per cell cycle mainly regulated by DNA replication initiation factors in eukaryotic cells. (intechopen.com)

His laboratory showed that cyclin-dependent kinases prevent pre-RC assembly in budding yeast by inhibiting ORC, and by regulating Cdc6 proteolysis and Mcm2-7 nuclear localisation. (royalsociety.org)
Cyclin-dependent kinases (CDKs) are key regulatory enzymes, each consisting of a catalytic CDK subunit and an activating cyclin subunit. (kegg.jp)

Ataxia telangiectasia and Rad3-related protein (ATR), the apical kinase of the intra-S-phase DNA damage response, plays a central role in safeguarding cells from replication stress and can therefore limit the efficacy of antimetabolite drug therapies. (nih.gov)
The ataxia telangiectasia mutated and Rad3-related (ATR) kinase is crucial for DNA damage and replication stress responses. (umn.edu)
METHODS: Here, we describe the cellular effects of pharmacological inhibition of the apical DDR kinase ATR (Ataxia Telangiectasia and Rad 3 related) with a highly selective inhibitor, VE-821, in hypoxic conditions and its potential as a radiosensitiser. (ox.ac.uk)

In animal cells, replication origins may seem to be randomly placed throughout the chromosome, sometimes even acting as ARSs, but local chromatin structure plays a large role in determining where replication will occur. (wikipedia.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)
p15 (PC4,Sub1) is involved not only in transcription, but also in DNA replication, damage repair, chromatin formation, and cell cycle regulation. (grassius.org)

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)
DNA replication and genome instability. (cancerrealitycheck.com)
DNA double-strand breaks (DSBs) induced by ionizing radiation (IR) and replication stress are the most deleterious lesions that lead to genomic instability and cellular transformation. (molcells.org)

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)
PP4IP interacts with PP4 complex, which is affected by DNA damage and cell cycle progression and decreases the dephosphorylational activity of PP4. (molcells.org)

Early experimental evidence on the regulation of DNA replication suggests that replication origins exist in one of two states during the cell cycle: a prereplicative state in G1 and a postreplicative state from the moment of initiation until passage through mitosis. (wikipedia.org)
In mitosis, ATR localizes to centromeres through Aurora A-regulated association with centromere protein F (CENP-F), allowing ATR to engage replication protein A (RPA)-coated centromeric R loops. (umn.edu)
Antimitotics damage cancer cells by blocking a process called mitosis (cell division), which prevents cancer cells from dividing and multiplying. (lls.org)
The pre-replication complex (pre-RC) assembly or the DNA replication licensing is the first step in DNA replication initiation, characterized by the sequential recruitment of ORCs, Cdc6, Cdt1 and MCMs to the DNA replication origins to form the pre-RC at the end of mitosis ( Bell and Dutta 2002 ). (intechopen.com)

Loading of the eukaryotic replicative helicase onto replication origins involves two MCM hexamers forming a double hexamer (DH) around duplex DNA. (bvsalud.org)
Evidence was recently presented of a crucial role for a helicase in protecting cells against chromosome breakage at normally occurring replication fork-stalling sites. (medscape.com)

Studying RNR2' s regulatory elements, he found those that were necessary to induce the production of higher protein levels in response to DNA damage and identified factors that bind these DNA elements to mediate the response of RNR2 to DNA damage. (the-scientist.com)
used siRNA to deplete TRAIP in cells exposed to agents that induce replication stress. (rupress.org)
Preclinical studies show M6620 (VX-970) synergizes with cisplatin to induce DNA damage and antitumor activity. (survivornet.com)

The replication origins are not distributed evenly throughout the chromosome. (wikipedia.org)
Despite key roles in sister chromatid cohesion and chromosome organization, the mechanism by which cohesin rings are loaded onto DNA is still unknown. (bvsalud.org)
TRAIP depletion also boosted the number of chromosome abnormalities and left cells more vulnerable to a DNA-damaging compound. (rupress.org)

Elledge had found that Rnr2 protein levels increased when yeast cells were grown in the presence of agents that damaged DNA. (the-scientist.com)
He found that RNR2 RNA levels increased dramatically, even more than the protein levels, upon exposure of cells to DNA damage and that mutations in RNR2 resulted in hypersensitivity to DNA damage. (the-scientist.com)
Those results led him to study how cells monitor roadblocks to replication and DNA damage, such as nicks and double-stranded breaks, and how the cell handles that information. (the-scientist.com)
Moreover, we demonstrate that Atm-deficient T cells display impaired proliferation capacity upon stimulation, due to replication stress. (nih.gov)
Antimetabolites mimic the building blocks of DNA or RNA that cancer cells need to survive and grow. (lls.org)
Antitumor antibiotics prevent cell division by either binding to DNA to prevent the cells from duplicating or inhibiting RNA synthesis. (lls.org)
Cells were washed in PBS and DNA was stained with propidium iodide. (cancerrealitycheck.com)
Re-expression of PIG3 effectively rescued the depression of DNA-PKcs in PIG3-depleted cells. (ijbs.com)
However, a compensatory feedback of increased mRNA expression of DNA-PKcs was formed in PIG3-depleted cells after a few passages or cell cycles of subculture, which led the recovery of the DNA-PKcs protein level and the consequent recovered efficiency of the DNA damage response. (ijbs.com)
HIV persistence may arise from ongoing residual virus replication and/or from latently-infected cells defined as the cellular reservoir in which long-lived resting memory CD4+ T cells harbouring an integrated but transcriptionally silent provirus represent the largest pool in the blood (Chomont et al. (europa.eu)
Furthermore, the ability of E4orf4, when expressed alone, to accumulate at DNA damage sites and to kill cancer cells is attenuated by chemical inhibition of PARP-1. (grandlacs-med-journal.com)
Inhibition of the DNA damage response (DDR) might be an effective way of sensitising hypoxic tumour cells to radiotherapy. (ox.ac.uk)
In order to examine the cytotoxicity of atrazine and the chance of atrazine-triggered DNA harm and DDR in individual cells human breasts epithelial MCF-10A cells had been selected as a report model within this research because atrazine was recommended to increase the incidence of breast cancer in female Sprague-Dawley rats [17]. (biobender.com)
Travis Stracker's research focuses on understanding how cells respond to DNA damage and maintain genomic stability. (cancer.gov)
Dr. Stracker's research focuses on understanding how cancer cells respond to radiotherapy, and other DNA damaging chemotherapies, and how these responses can be modulated for therapeutic gain. (cancer.gov)
One of the oxidative DNA lesions frequently generated upon exposure of cells to reactive oxygen species (ROS) is 7,8-dihydro-8-oxoguanine (8-oxoG) [ 13 ]. (biomedcentral.com)
Both overexpression and depletion of PP4IP impairs DSB repairs and sensitizes cells to genotoxic stress, suggesting timely inhibition of PP4 to be indispensable for cells in responding to DNA damage. (molcells.org)
Cells that are copying their DNA in preparation for division can undergo replication stress. (rupress.org)
have identified a protein that helps cells relieve this form of stress and continue DNA duplication ( 1 ). (rupress.org)
The protein also amassed at DNA lesions that the researchers created in human cells. (rupress.org)
Absence of TRAIP from cells compromises the response to replication stress. (rupress.org)
The cells also contained less single-stranded DNA and showed fewer signs of ATR activation. (rupress.org)
Cells remained longer in G2 and sometimes got stuck in that stage, suggesting that they couldn't complete DNA duplication. (rupress.org)
It is involved in the initial steps of the response of mammalian cells to DNA damage, and may facilitate subsequent steps in DNA repair (Mortusewicz et al. (grassius.org)
Oncogenes like MYCN and ALK result in increased replication stress in cancer cells, offering therapeutically exploitable options. (ugent.be)
Using RNA-Seq, proteomics and phosphoproteomics we characterize NB cell and tumour responses to ATR inhibition, identifying key components of the DNA damage response as ATR targets in NB cells. (ugent.be)

PARP-1 inhibition is important to Ad infection Lycopodine since treatment with a PARP inhibitor enhances replication efficiency. (grandlacs-med-journal.com)
When E4orf4 is expressed alone, it associates with poly(ADP-ribose) (PAR) chains and is recruited to DNA damage sites in a PARP-1-dependent manner. (grandlacs-med-journal.com)
Thus, the results presented here demonstrate a novel mechanism by which E4orf4 targets and inhibits DNA damage signaling through an association with PARP-1 for the benefit of the virus and impacting E4orf4-induced cancer cell death. (grandlacs-med-journal.com)
Here, we describe an association of E4orf4 Rabbit Polyclonal to PIK3CG with the DNA damage sensor poly(ADP-ribose) polymerase 1 (PARP-1). (grandlacs-med-journal.com)
PARP-1 inhibition assists E4orf4 in reducing Ad-induced DDR signaling and improves the efficiency of virus replication. (grandlacs-med-journal.com)
We show that E4orf4 interacts with PARP-1 and explore the consequences of this interaction during virus infection and under conditions of nonviral DNA damage. (grandlacs-med-journal.com)
PARP plays a key role in the process of DNA damage repair. (frontiersin.org)
The addition of PARP inhibitor veliparib with ATR inhibitor M6620 (VX-970) allows for impairment of DNA repair, the induction of a BRCA null phenotype, and potentiation of the antitumor activity of cisplatin. (survivornet.com)

The ATR-WEE1 kinase module plays a central role in response to replication stress. (bioinfor.com)
Through a genetic screen for suppressors of the Arabidopsis atr mutant, we found that loss of function of PRL1, a core subunit of the evolutionarily conserved MAC complex involved in alternative splicing, suppresses the hypersensitivity of atr and wee1 to replication stress. (bioinfor.com)
In line with the genetic and biochemical data, replication stress induces intron retention of cell cycle genes including CYCD1;1 and CYCD3;1, which is abolished in wee1 but restored in wee1 prl1. (bioinfor.com)
Remarkably, co-expressing the coding sequences of CYCD1;1 and CYCD3;1 partially restores the root length and HU response in wee1 prl1. (bioinfor.com)
These data suggested that the ATR-WEE1 module inhibits the MAC complex to regulate replication stress responses. (bioinfor.com)
consequently, WEE1(KO) and ATR(KO) roots are hypersensitive to replication-inhibitory drugs. (muni.cz)
Similarly, activation of CDK2 by inhibition or knockdown of the WEE1 kinase also depletes RRM2 and causes DNA damage and apoptosis. (figshare.com)

DNA replication control mechanisms cooperate to prevent the relicensing of replication origins and to activate cell cycle and DNA damage checkpoints. (wikipedia.org)
J-H Lee et al extensively investigated the participation of PIG3 in DNA damage checkpoints after UV irradiation or after treatment using the radiomimetic drug neocarzinostatin (NCS) ( 8 ). (ijbs.com)
Early precancerous lesions in affected person tissues aswell as particular oncogene activation in various tumor models have already been associated with DNA double-strand breaks (DSBs) as well as the activation of DNA-damage checkpoints [31]. (biobender.com)

IMPORTANCE Replication intermediates and ends of viral DNA genomes can be recognized by the cellular DNA damage response (DDR) network as DNA damage whose repair may Lycopodine lead to inhibition of virus replication. (grandlacs-med-journal.com)
HIF-1 stabilisation and transcriptional activity were both decreased in response to ATR inhibition. (ox.ac.uk)
ATR inhibition also produces robust responses in mouse models. (ugent.be)
These results suggest that NB patients, particularly in high-risk groups with oncogene-induced replication stress, may benefit from ATR inhibition as therapeutic intervention. (ugent.be)

The ATM gene encodes a large protein that belongs to a family of kinases possessing a highly conserved C-terminal kinase domain related to the phosphatidylinositol 3-kinase domain. (bmj.com)

John Diffley is known for his elegant use of genetics, biochemistry, molecular and cellular biology to elaborate the events that occur at origins of eukaryotic DNA replication throughout the cell cycle. (royalsociety.org)
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)
5 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, 50937, Germany. (nih.gov)
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)
Notably, PIG3 knockdown resulted in a striking depression of cellular DNA-PKcs protein level, and was accompanied by a downregulation of ATM. (ijbs.com)
These results provide a new insight into the mechanism of PIG3's functioning in DNA damage signaling and the regulation network of cellular DNA-PKcs expression homeostasis. (ijbs.com)
The role of the protein Mcl-1 in regulating the cellular response to DNA damage has resulted in the determination that drugs targeting Mcl-1 might serve as therapeutics in oral cancer. (actrec.gov.in)
Defects in the cellular response to DNA damage underlie rare diseases associated with cancer predisposition and are exploitable vulnerabilities for cancer therapy. (cancer.gov)
TLK activity is regulated by the DNA damage response and their depletion provokes innate immune signaling and enhances cellular sensitivity to DNA damaging agents. (cancer.gov)
Then we investigated that how PP4IP affects the cellular functions of PP4 by immunoprecipitation, immunofluorescence, and DNA double-strand break (DSB) repair assays. (molcells.org)

In this work we investigated the point of interaction between E4orf4 and the DDR as well as the mechanisms by which E4orf4 inhibits DNA damage signaling. (grandlacs-med-journal.com)

The histone acetyltransferase Tip60 regulates the apoptotic response to ultraviolet (UV) irradiation. (rupress.org)

The effect of ATR ablation is not due to altered cyclin-dependent kinase 1 (CDK1) activity, DNA damage responses, or unscheduled DNA synthesis but to loss of an ATR function at centromeres. (umn.edu)

This suppresses the ant-tumor immune response. (stanford.edu)
Elevated levels of replicative stress in gynecological cancers arising from uncontrolled oncogenic activation, loss of key tumor suppressors, and frequent defects in the DNA repair machinery are an intrinsic vulnerability for therapeutic exploitation. (bmj.com)
Cdc7 is a key regulator of DNA replication and is involved in the DDR network, making it a compelling emerging target for the potential treatment of a broad range of tumor types. (salesandmarketingnetwork.com)
Based on the heterogeneity within a specific tumor type, a combination of genomic alterations defines the cancer subtype, biologic behavior, and in some cases, response to therapeutics. (hindawi.com)

Thus, CDKs serve a dual role in the regulation of eukaryotic DNA replication: elevated CDK activity initiates replication at the origins and prevents rereplication by inhibiting origin re-licensing. (wikipedia.org)

Forsburg takes a holistic approach to studying how DNA replication stress contributes to genome stability. (usc.edu)
DNA damage response is a fundamental mechanism to maintain genome stability. (bioinfor.com)
Mortusewicz O, Evers B, Helleday T. PC4 promotes genome stability and DNA repair through binding of ssDNA at DNA damage sites. (grassius.org)

SRA141 is a potent, selective, orally bioavailable small molecule inhibitor of Cell division cycle 7 kinase (Cdc7). (salesandmarketingnetwork.com)

The p53-inducible gene 3 (PIG3) recently has been reported to be a new player in DNA damage signaling and response, but the crucial mechanism remains unclear. (ijbs.com)
In the present study, the potential mechanism of PIG3 participation in the DNA damage response induced by ionizing radiation (IR) was investigated in multiple cell lines with depleted expression of PIG3 transiently or stably by the small interference RNA and lentivirus-mediated shRNA expression strategies. (ijbs.com)

determined that TRAIP's ubiquitylating activity is essential for resolving replication stress, whereas the PIP box isn't. (rupress.org)

We've identified a new factor that has an important role in the response to replication stress," says Mailand. (rupress.org)
The study suggests that TRAIP promotes the resolution of replication stress by spurring the formation of RPA-covered single-stranded DNA and ATR activation. (rupress.org)
10] Fragile sites may be DNA regions particularly sensitive to replicative stress. (medscape.com)

Origin licensing is the preliminary step for normal replication initiation during late G1 and early S phase and involves the recruitment of the pre-replicative complex (pre-RC) to the replication origins. (wikipedia.org)
Licensing begins with the binding of the multi-subunit ATPase, the origin recognition complex (ORC), to the DNA at the replication origins. (wikipedia.org)
Origins of replication alternate between these two distinct states during the cell cycle. (wikipedia.org)
A licensing factor which is required for replication initiation binds to origins in the prereplicative state. (wikipedia.org)
The precise regulations of pre-RC protein levels and assembly are effective ways to prevent reassembly of de novo MCM2-7 onto the replicated origins to re-license and re-replicate the genomic DNA in the subsequent phases of the same cell cycle ( Figure 1) . (intechopen.com)

Additionally, cyclin-dependent kinase promotes initiation by phosphorylating Sld2 and Sld3. (royalsociety.org)
In this chapter, we mainly discuss the coordination regulations between DNA replication initiation and other cell cycle events that ensure genomic integrity. (intechopen.com)

As a start to designing those gene-targeting tools, Elledge, now a professor of genetics at Harvard Medical School, began by trying to clone the mammalian homolog of recA , a bacterial gene required for DNA repair via recombination. (the-scientist.com)
ATR additionally facilitates homologous recombination repair through modulation of the p53-replication protein A (p53-RPA) complex bound to single-stranded deoxyribonucleic acid (ssDNA) during the DNA repair process. (survivornet.com)

3 , 4 The ATM gene is located at 11q22-23, spans 184 kb of genomic DNA, and has 66 exons. (bmj.com)
Nonstructural protein 1 (NS1) is a DNA-binding protein involved in gene transcription. (medscape.com)
We observe that each gene and its products have a unique set of DNA, RNA or protein motifs that encode a regulatory program to define the logical circuitry that guides the life cycle of these biomolecules, from transcription to degradation. (biomedcentral.com)

Using this inhibitor we have also demonstrated for the first time a link between ATR and the key regulator of the hypoxic response, HIF-1. (ox.ac.uk)

DNA repair is a normal and vital process within the cell. (lls.org)
Without this repair process, the cancer cell is much more susceptible to damage and cannot grow. (lls.org)
Driven by a profound interest in the nuclear events that influence human cell health and disease, I dedicated four years to serving as a European Framework for DNA Repair Postdoctoral Research Fellow. (westminster.ac.uk)
This role was based at a pioneering lab in DNA mismatch repair within the Institute of Molecular Cancer Research at the University of Zurich. (westminster.ac.uk)
The human mutY homolog (hMYH) is a base excision repair DNA glycosylase that excises adenines or 2-hydroxyadenines that are mispaired with guanine or 7,8-dihydro-8-oxoguanine (8-oxoG). (biomedcentral.com)
PC4 played a role in the extremely early reaction of DNA damage by identifying single-stranded DNA damage, and could be recruited early to the DNA damage site, thus possibly initiating or promoting the subsequent steps of DNA damage and repair. (grassius.org)

Recent studies indicate that ATM is activated primarily in response to double strand breaks and may be considered a caretaker of the genome. (bmj.com)

Moreover, we observed that hMYH was essential for the accumulation of hTopBP1 on damaged DNA, where hTopBP1 interacts with hRad9, a component of the Rad9-Hus1-Rad1 complex. (biomedcentral.com)
Then hTopBP1 interacts with ATR-ATRIP through its ATR-activating domain (AD) and stimulates ATR kinase activity [ 8 , 9 ]. (biomedcentral.com)

Our results establish the molecular basis for cohesin loading onto DNA. (bvsalud.org)
A major line of research in the lab focuses on understanding the molecular functions of the Tousled-like kinases (TLKs), TLK1 and TLK2. (cancer.gov)

A cell may run short of nucleotides to plug into the new DNA strands, for example, or the replication machinery might run into a section of DNA that is damaged or tricky to copy. (rupress.org)

In turn, RPA coats single strands and draws in the ATR kinase, which halts the cell cycle and triggers other responses that protect the genome while the cell removes the blockage ( 4 ). (rupress.org)

The specific changes on the DNA upon UV exposure are different from those induced by γ irradiation, mostly resulting in chemical modifications of single DNA strands such as cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts ( Balajee and Bohr, 2000 ). (rupress.org)

Anatomy8

Organisms4

Diseases1

Chemicals and Drugs66

Analytical, Diagnostic and Therapeutic Techniques and Equipment5

Phenomena and Processes40

Information Science3

Health Care1

Proteins28

Checkpoint18

CHK18

Forks8

Protein kinase2

Inhibitors4

Phosphorylation8

Tyrosine kinase in1

Arrest5

Pathway2

Signal transduction1

Eukaryotic cells6

Cyclin-depende2

Ataxia telangiectasia3

Chromatin3

Instability3

Progression2

Mitosis4

Helicase2

Induce3

Chromosome3

Cells26

PARP8

Wee17

Checkpoints3

Inhibition4

Phosphatidylinositol1

Cellular10

Inhibits1

Histone1

Synthesis1

Tumor4

Cdks1

Stability3

Cdc71

Mechanism2

Resolving replication stress1

Stress3

Origins5

Initiation2

Recombination2

Gene3

Regulator1

Repair6

Double strand breaks1

Interacts2

Molecular2

Machinery1

Triggers1

Strands1