The Experts below are selected from a list of 5166 Experts worldwide ranked by ideXlab platform
Vassilis C. Zoumpourlis - One of the best experts on this subject based on the ideXlab platform.
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oncogene induced senescence is part of the tumorigenesis barrier imposed by DNA Damage Checkpoints
Nature, 2006Co-Authors: J. Bártková, Nousin Rezaei, Panagiotis Karakaidos, Leandros Vassilios F. Vassiliou, Michalis Liontos, Evangelos Kolettas, Natalia Issaeva, Katerina Niforou, Dimitris Kletsas, Vassilis C. ZoumpourlisAbstract:Cancer is commonly thought of as uncontrolled cellular proliferation, but in the early stages of many cancers, oncogene expression is associated with cellular senescence. A possible explanation for this has now been found. Two groups report a link between oncogene-induced senescence and the DNA Damage response. Activated oncogenes can cause aberrant DNA replication and thereby DNA Damage that can lead to cell senescence. Cellular senescence was found previously to be a barrier to tumorigenesis in vivo, so oncogene-induced senescence may be an innate defence against cancer. But its effectiveness is often disabled by further mutations. Understanding the relationship between cell senescence and tumour formation may aid in the development of diagnostic and prognostic tools based on senescence markers. One of two papers linking oncogene-induced senescence and the DNA Damage response. Activated oncogenes can cause aberrant DNA replication and thereby DNA Damage, which leads to cellular senescence. This response can block tumour progression, but is often disabled by further alterations. Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA Damage checkpoint and thereby to apoptosis or cell cycle arrest1,2, whereas a second barrier is mediated by oncogene-induced senescence3,4,5,6. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA Damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.
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Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA Damage Checkpoints
Nature, 2006Co-Authors: J. Bártková, Nousin Rezaei, Panagiotis Karakaidos, Leandros Vassilios F. Vassiliou, Michalis Liontos, Evangelos Kolettas, Natalia Issaeva, Katerina Niforou, Dimitris Kletsas, Vassilis C. ZoumpourlisAbstract:Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA Damage checkpoint and thereby to apoptosis or cell cycle arrest, whereas a second barrier is mediated by oncogene-induced senescence. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA Damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.
Aziz Sancar - One of the best experts on this subject based on the ideXlab platform.
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coupling of human DNA excision repair and the DNA Damage checkpoint in a defined in vitro system
Journal of Biological Chemistry, 2014Co-Authors: Laura A Lindseyboltz, Michael G Kemp, Joyce T Reardon, Vanessa Derocco, Ravi R Iyer, Paul Modrich, Aziz SancarAbstract:DNA repair and DNA Damage Checkpoints work in concert to help maintain genomic integrity. In vivo data suggest that these two global responses to DNA Damage are coupled. It has been proposed that the canonical 30 nucleotide single-stranded DNA gap generated by nucleotide excision repair is the signal that activates the ATR-mediated DNA Damage checkpoint response and that the signal is enhanced by gap enlargement by EXO1 (exonuclease 1) 5′ to 3′ exonuclease activity. Here we have used purified core nucleotide excision repair factors (RPA, XPA, XPC, TFIIH, XPG, and XPF-ERCC1), core DNA Damage checkpoint proteins (ATR-ATRIP, TopBP1, RPA), and DNA Damaged by a UV-mimetic agent to analyze the basic steps of DNA Damage checkpoint response in a biochemically defined system. We find that checkpoint signaling as measured by phosphorylation of target proteins by the ATR kinase requires enlargement of the excision gap generated by the excision repair system by the 5′ to 3′ exonuclease activity of EXO1. We conclude that, in addition to Damaged DNA, RPA, XPA, XPC, TFIIH, XPG, XPF-ERCC1, ATR-ATRIP, TopBP1, and EXO1 constitute the minimum essential set of factors for ATR-mediated DNA Damage checkpoint response.
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rna polymerase the most specific Damage recognition protein in cellular responses to DNA Damage
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Laura A Lindseyboltz, Aziz SancarAbstract:DNA Damage induces a number of cellular responses in human cells, including DNA repair, transcriptional reprogramming, delay of cell cycle progression, and apoptosis (1). The most common DNA lesions fall into two broad groups: base lesions and single- and double-strand breaks. Both types of lesions are detected by Damage sensors that initiate various response reactions. A central question in understanding these responses is the identity of the Damage sensor. The study by Derheimer et al. (2) in a recent issue of PNAS, together with previous studies, suggests that RNA polymerase II (RNAP II) stalled at a Damaged DNA base may constitute the most specific signal for DNA repair, DNA Damage Checkpoints, and apoptosis (Fig. 1). We suggest that RNAP II is an ideal Damage sensor because it has the highest selectivity of all known DNA Damage recognition proteins.
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cryptochrome circadian cycle cell cycle Checkpoints and cancer
Cancer Research, 2005Co-Authors: Michele Gauger, Aziz SancarAbstract:It has been reported that disruption of the circadian clock may lead to increased risk of breast cancer in humans and to a high rate or ionizing radiation-induced tumors and mortality in mice. Cryptochrome 1 and cryptochrome 2 proteins are core components of the mammalian circadian clock and mice mutated in both genes are arrhythmic. We tested Cry1-/- Cry2-/- mice and fibroblasts derived from these mice for radiation-induced cancer and killing and DNA Damage Checkpoints and killing, respectively. We find that the mutant mice are indistinguishable from the wild-type controls with respect to radiation-induced morbidity and mortality. Similarly, the Cry1-/- Cry2-/-mutant fibroblasts are indistinguishable from the wild-type controls with respect to their sensitivity to ionizing radiation and UV radiation and ionizing radiation-induced DNA Damage checkpoint response. Our data suggest that disruption of the circadian clock in itself does not compromise mammalian DNA repair and DNA Damage Checkpoints and does not predispose mice to spontaneous and ionizing radiation-induced cancers. We conclude that the effect of circadian clock disruption on cellular response to DNA Damage and cancer predisposition in mice may depend on the mechanism by which the clock is disrupted.
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molecular mechanisms of mammalian DNA repair and the DNA Damage Checkpoints
Annual Review of Biochemistry, 2004Co-Authors: Aziz Sancar, Laura A Lindseyboltz, Keziban Unsalkacmaz, Stuart LinnAbstract:DNA Damage is a relatively common event in the life of a cell and may lead to mutation, cancer, and cellular or organismic death. Damage to DNA induces several cellular responses that enable the cell either to eliminate or cope with the Damage or to activate a programmed cell death process, presumably to eliminate cells with potentially catastrophic mutations. These DNA Damage response reactions include: (a) removal of DNA Damage and restoration of the continuity of the DNA duplex; (b) activation of a DNA Damage checkpoint, which arrests cell cycle progression so as to allow for repair and prevention of the transmission of Damaged or incompletely replicated chromosomes; (c) transcriptional response, which causes changes in the transcription profile that may be beneficial to the cell; and (d) apoptosis, which eliminates heavily Damaged or seriously deregulated cells. DNA repair mechanisms include direct repair, base excision repair, nucleotide excision repair, double-strand break repair, and cross-link repair. The DNA Damage Checkpoints employ Damage sensor proteins, such as ATM, ATR, the Rad17-RFC complex, and the 9-1-1 complex, to detect DNA Damage and to initiate signal transduction cascades that employ Chk1 and Chk2 Ser/Thr kinases and Cdc25 phosphatases. The signal transducers activate p53 and inactivate cyclin-dependent kinases to inhibit cell cycle progression from G1 to S (the G1/S checkpoint), DNA replication (the intra-S checkpoint), or G2 to mitosis (the G2/M checkpoint). In this review the molecular mechanisms of DNA repair and the DNA Damage Checkpoints in mammalian cells are analyzed.
J. Bártková - One of the best experts on this subject based on the ideXlab platform.
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oncogene induced senescence is part of the tumorigenesis barrier imposed by DNA Damage Checkpoints
Nature, 2006Co-Authors: J. Bártková, Nousin Rezaei, Panagiotis Karakaidos, Leandros Vassilios F. Vassiliou, Michalis Liontos, Evangelos Kolettas, Natalia Issaeva, Katerina Niforou, Dimitris Kletsas, Vassilis C. ZoumpourlisAbstract:Cancer is commonly thought of as uncontrolled cellular proliferation, but in the early stages of many cancers, oncogene expression is associated with cellular senescence. A possible explanation for this has now been found. Two groups report a link between oncogene-induced senescence and the DNA Damage response. Activated oncogenes can cause aberrant DNA replication and thereby DNA Damage that can lead to cell senescence. Cellular senescence was found previously to be a barrier to tumorigenesis in vivo, so oncogene-induced senescence may be an innate defence against cancer. But its effectiveness is often disabled by further mutations. Understanding the relationship between cell senescence and tumour formation may aid in the development of diagnostic and prognostic tools based on senescence markers. One of two papers linking oncogene-induced senescence and the DNA Damage response. Activated oncogenes can cause aberrant DNA replication and thereby DNA Damage, which leads to cellular senescence. This response can block tumour progression, but is often disabled by further alterations. Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA Damage checkpoint and thereby to apoptosis or cell cycle arrest1,2, whereas a second barrier is mediated by oncogene-induced senescence3,4,5,6. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA Damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.
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Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA Damage Checkpoints
Nature, 2006Co-Authors: J. Bártková, Nousin Rezaei, Panagiotis Karakaidos, Leandros Vassilios F. Vassiliou, Michalis Liontos, Evangelos Kolettas, Natalia Issaeva, Katerina Niforou, Dimitris Kletsas, Vassilis C. ZoumpourlisAbstract:Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA Damage checkpoint and thereby to apoptosis or cell cycle arrest, whereas a second barrier is mediated by oncogene-induced senescence. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA Damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.
Rene H Medema - One of the best experts on this subject based on the ideXlab platform.
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the same only different DNA Damage Checkpoints and their reversal throughout the cell cycle
Journal of Cell Science, 2015Co-Authors: Indra A Shaltiel, Lenno Krenning, Wytse Bruinsma, Rene H MedemaAbstract:Cell cycle Checkpoints activated by DNA double-strand breaks (DSBs) are essential for the maintenance of the genomic integrity of proliferating cells. Following DNA Damage, cells must detect the break and either transiently block cell cycle progression, to allow time for repair, or exit the cell cycle. Reversal of a DNA-Damage-induced checkpoint not only requires the repair of these lesions, but a cell must also prevent permanent exit from the cell cycle and actively terminate checkpoint signalling to allow cell cycle progression to resume. It is becoming increasingly clear that despite the shared mechanisms of DNA Damage detection throughout the cell cycle, the checkpoint and its reversal are precisely tuned to each cell cycle phase. Furthermore, recent findings challenge the dogmatic view that complete repair is a precondition for cell cycle resumption. In this Commentary, we highlight cell-cycle-dependent differences in checkpoint signalling and recovery after a DNA DSB, and summarise the molecular mechanisms that underlie the reversal of DNA Damage Checkpoints, before discussing when and how cell fate decisions after a DSB are made.
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human prostate epithelium lacks wee1a mediated DNA Damage induced checkpoint enforcement
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Taija Kiviharjuaf M Hallstrom, Sari Jaamaa, Mia Monkkonen, Karita Peltonen, Leif C Andersson, Rene H Medema, Donna M Peehl, Marikki LaihoAbstract:Cellular DNA Damage triggers the DNA Damage response pathway and leads to enforcement of cell cycle Checkpoints, which are essential for the maintenance of genomic integrity and are activated in early stages of tumorigenesis. A special feature of prostate cancer is its high incidence and multifocality. To address the functionality of DNA Damage Checkpoints in the prostate, we analyzed the responses of human primary prostate epithelial cells (HPECs) and freshly isolated human prostate tissues to γ-irradiation. We find that γ-irradiation activates the ataxia telangiectasia mutated-associated DNA Damage response pathway in the HPECs but that the clearance of phosphorylated histone H2AX (γH2AX) foci is delayed. Surprisingly, γ-irradiated HPECs were unable to enforce cell cycle checkpoint arrest and had sustained cyclin-dependent kinase 2 (Cdk2)-associated kinase activity because of a lack of inhibitory Cdk phosphorylation by Wee1A tyrosine kinase. We further show that HPECs express low levels of Wee1A and that ectopic Wee1A efficiently rescues the Checkpoints. We recapitulate the absence of checkpoint responses in epithelium of ex vivo irradiated human prostate tissue despite robust induction of γH2AX. The findings show that prostate epithelium has a surprising inability to control checkpoint arrest, the lack of which may predispose to accrual of DNA lesions.
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polo like kinase 1 controls proteasome dependent degradation of claspin during checkpoint recovery
Current Biology, 2006Co-Authors: Ivan Mamely, Rene H Medema, Marcel A T M Van Vugt, Veronique A J Smits, Jennifer I Semple, Bennie Lemmens, Anastassis Perrakis, Raimundo FreireAbstract:DNA-Damage Checkpoints maintain genomic integrity by mediating a cell-cycle delay in response to genotoxic stress or stalled replication forks. In response to Damage, the checkpoint kinase ATR phosphorylates and activates its effector kinase Chk1 in a process that critically depends on Claspin [1]. However, it is not known how exactly this kinase cascade is silenced. Here we demonstrate that the abundance of Claspin is regulated through proteasomal degradation. In response to DNA Damage, Claspin is transiently stabilized, and its expression depends on Chk1 kinase activity. In addition, we show that Claspin is degraded upon mitotic entry, a process that depends on the β-TrCP-SCF ubiquitin ligase and Polo-like kinase-1 (Plk1). We demonstrate that Claspin interacts with both β-TrCP and Plk1 and that inactivation of these components or the β-TrCP recognition motif in Claspin prevents its mitotic degradation. Interestingly, expression of a nondegradable Claspin mutant inhibits recovery from a DNA-Damage-induced checkpoint arrest. Thus, we conclude that Claspin levels are tightly regulated, both during unperturbed cell cycles and after DNA Damage. Moreover, our data demonstrate that the degradation of Claspin at the onset of mitosis is an essential step for the recovery of a cell from a DNA-Damage-induced cell-cycle arrest.
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getting in and out of mitosis with polo like kinase 1
Oncogene, 2005Co-Authors: Marcel A T M Van Vugt, Rene H MedemaAbstract:Research in different species has shown that Polo-like kinases are essential for successful cell division. In human cells, Polo-like kinase-1 (Plk1) has been implicated in the regulation of different processes, including mitotic entry, spindle formation and cytokinesis. Recently, a range of new downstream targets of Plk1 has been identified, as well as a molecular mechanism that explains recruitment of Plk1 to potential substrate proteins through its polo-box domain. On the basis of these reports, we discuss possible mechanisms by which Polo-like kinases can exert their multiple functions during mitosis. Polo-like kinases also function in DNA Damage Checkpoints. Plk1 has been shown to be a target of the G2 DNA Damage checkpoint, while Cdc5, the Polo-like kinase in Saccharomyces cerevisiae, has long been known to be required for adaptation to persistent DNA Damage. Just recently, a similar requirement for Polo-like kinases during checkpoint adaptation was demonstrated in multicellular organisms. Moreover, Plk1 was also shown to be required for checkpoint recovery following checkpoint inactivation, that is, in cells where the Damage is completely repaired. Thus, Plk1 appears to play a role at multiple points during a restart of the cell cycle following DNA Damage. Based on these novel observations, we discuss possible consequences of using Plk1 as a target in anticancer strategies.
Nousin Rezaei - One of the best experts on this subject based on the ideXlab platform.
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oncogene induced senescence is part of the tumorigenesis barrier imposed by DNA Damage Checkpoints
Nature, 2006Co-Authors: J. Bártková, Nousin Rezaei, Panagiotis Karakaidos, Leandros Vassilios F. Vassiliou, Michalis Liontos, Evangelos Kolettas, Natalia Issaeva, Katerina Niforou, Dimitris Kletsas, Vassilis C. ZoumpourlisAbstract:Cancer is commonly thought of as uncontrolled cellular proliferation, but in the early stages of many cancers, oncogene expression is associated with cellular senescence. A possible explanation for this has now been found. Two groups report a link between oncogene-induced senescence and the DNA Damage response. Activated oncogenes can cause aberrant DNA replication and thereby DNA Damage that can lead to cell senescence. Cellular senescence was found previously to be a barrier to tumorigenesis in vivo, so oncogene-induced senescence may be an innate defence against cancer. But its effectiveness is often disabled by further mutations. Understanding the relationship between cell senescence and tumour formation may aid in the development of diagnostic and prognostic tools based on senescence markers. One of two papers linking oncogene-induced senescence and the DNA Damage response. Activated oncogenes can cause aberrant DNA replication and thereby DNA Damage, which leads to cellular senescence. This response can block tumour progression, but is often disabled by further alterations. Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA Damage checkpoint and thereby to apoptosis or cell cycle arrest1,2, whereas a second barrier is mediated by oncogene-induced senescence3,4,5,6. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA Damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.
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Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA Damage Checkpoints
Nature, 2006Co-Authors: J. Bártková, Nousin Rezaei, Panagiotis Karakaidos, Leandros Vassilios F. Vassiliou, Michalis Liontos, Evangelos Kolettas, Natalia Issaeva, Katerina Niforou, Dimitris Kletsas, Vassilis C. ZoumpourlisAbstract:Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA Damage checkpoint and thereby to apoptosis or cell cycle arrest, whereas a second barrier is mediated by oncogene-induced senescence. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA Damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.