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  1. Article: The Replication Stress Response on a Narrow Path Between Genomic Instability and Inflammation.

    Técher, Hervé / Pasero, Philippe

    Frontiers in cell and developmental biology

    2021  Volume 9, Page(s) 702584

    Abstract: The genome of eukaryotic cells is particularly at risk during the S phase of the cell cycle, when megabases of chromosomal DNA are unwound to generate two identical copies of the genome. This daunting task is executed by thousands of micro-machines ... ...

    Abstract The genome of eukaryotic cells is particularly at risk during the S phase of the cell cycle, when megabases of chromosomal DNA are unwound to generate two identical copies of the genome. This daunting task is executed by thousands of micro-machines called replisomes, acting at fragile structures called replication forks. The correct execution of this replication program depends on the coordinated action of hundreds of different enzymes, from the licensing of replication origins to the termination of DNA replication. This review focuses on the mechanisms that ensure the completion of DNA replication under challenging conditions of endogenous or exogenous origin. It also covers new findings connecting the processing of stalled forks to the release of small DNA fragments into the cytoplasm, activating the cGAS-STING pathway. DNA damage and fork repair comes therefore at a price, which is the activation of an inflammatory response that has both positive and negative impacts on the fate of stressed cells. These new findings have broad implications for the etiology of interferonopathies and for cancer treatment.
    Language English
    Publishing date 2021-06-25
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2737824-X
    ISSN 2296-634X
    ISSN 2296-634X
    DOI 10.3389/fcell.2021.702584
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Replication stress: from chromatin to immunity and beyond.

    Lin, Yea-Lih / Pasero, Philippe

    Current opinion in genetics & development

    2021  Volume 71, Page(s) 136–142

    Abstract: Replication stress (RS) is a hallmark of cancer cells that is associated with increased genomic instability. RS occurs when replication forks encounter obstacles along the DNA. Stalled forks are signaled by checkpoint kinases that prevent fork collapse ... ...

    Abstract Replication stress (RS) is a hallmark of cancer cells that is associated with increased genomic instability. RS occurs when replication forks encounter obstacles along the DNA. Stalled forks are signaled by checkpoint kinases that prevent fork collapse and coordinate fork repair pathways. Fork restart also depends on chromatin remodelers to increase the accessibility of nascent chromatin to recombination and repair factors. In this review, we discuss recent findings on the causes and consequences of RS, with a focus on endogenous replication impediments and their impact on fork velocity. We also discuss recent studies on the interplay between stalled forks and innate immunity, which extends the RS response beyond cell boundaries and opens new avenues for cancer therapy.
    MeSH term(s) Chromatin/genetics ; DNA/metabolism ; DNA Replication/genetics ; DNA-Binding Proteins/genetics ; Genomic Instability/genetics ; Humans
    Chemical Substances Chromatin ; DNA-Binding Proteins ; DNA (9007-49-2)
    Language English
    Publishing date 2021-08-26
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1077312-5
    ISSN 1879-0380 ; 0959-437X
    ISSN (online) 1879-0380
    ISSN 0959-437X
    DOI 10.1016/j.gde.2021.08.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Top1p targeting by Fob1p at the ribosomal Replication Fork Barrier does not account for camptothecin sensitivity in

    Pourali, Pardis / Pasero, Philippe / Pardo, Benjamin

    microPublication biology

    2022  Volume 2022

    Abstract: Camptothecin (CPT) is a specific inhibitor of the DNA topoisomerase I (Top1p), currently used in cancer therapy, which induces DNA damage and cell death. Top1p is highly active at the repeated ribosomal ... ...

    Abstract Camptothecin (CPT) is a specific inhibitor of the DNA topoisomerase I (Top1p), currently used in cancer therapy, which induces DNA damage and cell death. Top1p is highly active at the repeated ribosomal DNA
    Language English
    Publishing date 2022-01-19
    Publishing country United States
    Document type Journal Article
    ISSN 2578-9430
    ISSN (online) 2578-9430
    DOI 10.17912/micropub.biology.000514
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Sir2 takes affirmative action to ensure equal opportunity in replication origin licensing.

    Lengronne, Armelle / Pasero, Philippe

    Proceedings of the National Academy of Sciences of the United States of America

    2020  Volume 117, Issue 29, Page(s) 16723–16725

    MeSH term(s) DNA Replication ; Euchromatin ; Public Policy ; Replication Origin ; Saccharomyces cerevisiae ; Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Sirtuin 2
    Chemical Substances Euchromatin ; Silent Information Regulator Proteins, Saccharomyces cerevisiae ; SIR2 protein, S cerevisiae (EC 3.5.1.-) ; Sirtuin 2 (EC 3.5.1.-)
    Language English
    Publishing date 2020-06-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2010001117
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Top1 and Top2 promote replication fork arrest at a programmed pause site.

    Larcher, Mélanie V / Pasero, Philippe

    Genes & development

    2020  Volume 34, Issue 1-2, Page(s) 1–3

    Abstract: Programmed fork pausing is a complex process allowing cells to arrest replication forks at specific loci in a polar manner. Studies in budding yeast and other model organisms indicate that such replication fork barriers do not act as roadblocks passively ...

    Abstract Programmed fork pausing is a complex process allowing cells to arrest replication forks at specific loci in a polar manner. Studies in budding yeast and other model organisms indicate that such replication fork barriers do not act as roadblocks passively impeding fork progression but rather elicit complex interactions between fork and barrier components. In this issue of
    MeSH term(s) Cell Cycle Proteins ; DNA Replication ; DNA Topoisomerases, Type I ; DNA-Binding Proteins ; Saccharomyces cerevisiae Proteins
    Chemical Substances Cell Cycle Proteins ; DNA-Binding Proteins ; Saccharomyces cerevisiae Proteins ; DNA Topoisomerases, Type I (EC 5.99.1.2)
    Language English
    Publishing date 2020-01-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 806684-x
    ISSN 1549-5477 ; 0890-9369
    ISSN (online) 1549-5477
    ISSN 0890-9369
    DOI 10.1101/gad.335463.119
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: The Replication Stress Response on a Narrow Path Between Genomic Instability and Inflammation

    Hervé Técher / Philippe Pasero

    Frontiers in Cell and Developmental Biology, Vol

    2021  Volume 9

    Abstract: The genome of eukaryotic cells is particularly at risk during the S phase of the cell cycle, when megabases of chromosomal DNA are unwound to generate two identical copies of the genome. This daunting task is executed by thousands of micro-machines ... ...

    Abstract The genome of eukaryotic cells is particularly at risk during the S phase of the cell cycle, when megabases of chromosomal DNA are unwound to generate two identical copies of the genome. This daunting task is executed by thousands of micro-machines called replisomes, acting at fragile structures called replication forks. The correct execution of this replication program depends on the coordinated action of hundreds of different enzymes, from the licensing of replication origins to the termination of DNA replication. This review focuses on the mechanisms that ensure the completion of DNA replication under challenging conditions of endogenous or exogenous origin. It also covers new findings connecting the processing of stalled forks to the release of small DNA fragments into the cytoplasm, activating the cGAS-STING pathway. DNA damage and fork repair comes therefore at a price, which is the activation of an inflammatory response that has both positive and negative impacts on the fate of stressed cells. These new findings have broad implications for the etiology of interferonopathies and for cancer treatment.
    Keywords DNA replication dynamics ; fork progression ; fork processing ; fork reversal ; cGAS-STING ; inflammation ; Biology (General) ; QH301-705.5
    Subject code 612
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Impact of R-loops on oncogene-induced replication stress in cancer cells.

    Heuzé, Jonathan / Lin, Yea-Lih / Lengronne, Armelle / Poli, Jérôme / Pasero, Philippe

    Comptes rendus biologies

    2023  Volume 346, Page(s) 95–105

    Abstract: Replication stress is an alteration in the progression of replication forks caused by a variety of events of endogenous or exogenous origin. In precancerous lesions, this stress is exacerbated by the deregulation of oncogenic pathways, which notably ... ...

    Abstract Replication stress is an alteration in the progression of replication forks caused by a variety of events of endogenous or exogenous origin. In precancerous lesions, this stress is exacerbated by the deregulation of oncogenic pathways, which notably disrupts the coordination between replication and transcription, and leads to genetic instability and cancer development. It is now well established that transcription can interfere with genome replication in different ways, such as head-on collisions between polymerases, accumulation of positive DNA supercoils or formation of R-loops. These structures form during transcription when nascent RNA reanneals with DNA behind the RNA polymerase, forming a stable DNA:RNA hybrid. In this review, we discuss how these different cotranscriptional processes disrupt the progression of replication forks and how they contribute to genetic instability in cancer cells.
    MeSH term(s) Transcription, Genetic ; R-Loop Structures ; DNA Replication/genetics ; DNA ; Oncogenes/genetics ; RNA ; Neoplasms/genetics
    Chemical Substances DNA (9007-49-2) ; RNA (63231-63-0)
    Language English
    Publishing date 2023-09-22
    Publishing country France
    Document type Journal Article ; Review
    ZDB-ID 2072863-3
    ISSN 1768-3238 ; 1631-0691
    ISSN (online) 1768-3238
    ISSN 1631-0691
    DOI 10.5802/crbiol.123
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Overexpression of the Fork Protection Complex: a strategy to tolerate oncogene-induced replication stress in cancer cells.

    Pasero, Philippe / Tourrière, Hélène

    Molecular & cellular oncology

    2019  Volume 6, Issue 4, Page(s) 1607455

    Abstract: Oncogene-induced replication stress (RS) plays an active role in tumorigenesis by promoting genomic instability but is also a challenge for cell proliferation. Recent evidence indicates that different types of cancer cells adapt to RS by overexpressing ... ...

    Abstract Oncogene-induced replication stress (RS) plays an active role in tumorigenesis by promoting genomic instability but is also a challenge for cell proliferation. Recent evidence indicates that different types of cancer cells adapt to RS by overexpressing components of the ATR-CHK1 pathway that promote fork progression in a checkpoint-independent manner.
    Language English
    Publishing date 2019-05-07
    Publishing country United States
    Document type Journal Article
    ISSN 2372-3556
    ISSN 2372-3556
    DOI 10.1080/23723556.2019.1607455
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Artificial Intelligence ECG Analysis in Patients with Short QT Syndrome to Predict Life-Threatening Arrhythmic Events.

    Pasero, Eros / Gaita, Fiorenzo / Randazzo, Vincenzo / Meynet, Pierre / Cannata, Sergio / Maury, Philippe / Giustetto, Carla

    Sensors (Basel, Switzerland)

    2023  Volume 23, Issue 21

    Abstract: Short QT syndrome (SQTS) is an inherited cardiac ion-channel disease related to an increased risk of sudden cardiac death (SCD) in young and otherwise healthy individuals. SCD is often the first clinical presentation in patients with SQTS. However, ... ...

    Abstract Short QT syndrome (SQTS) is an inherited cardiac ion-channel disease related to an increased risk of sudden cardiac death (SCD) in young and otherwise healthy individuals. SCD is often the first clinical presentation in patients with SQTS. However, arrhythmia risk stratification is presently unsatisfactory in asymptomatic patients. In this context, artificial intelligence-based electrocardiogram (ECG) analysis has never been applied to refine risk stratification in patients with SQTS. The purpose of this study was to analyze ECGs from SQTS patients with the aid of different AI algorithms to evaluate their ability to discriminate between subjects with and without documented life-threatening arrhythmic events. The study group included 104 SQTS patients, 37 of whom had a documented major arrhythmic event at presentation and/or during follow-up. Thirteen ECG features were measured independently by three expert cardiologists; then, the dataset was randomly divided into three subsets (training, validation, and testing). Five shallow neural networks were trained, validated, and tested to predict subject-specific class (non-event/event) using different subsets of ECG features. Additionally, several deep learning and machine learning algorithms, such as Vision Transformer, Swin Transformer, MobileNetV3, EfficientNetV2, ConvNextTiny, Capsule Networks, and logistic regression were trained, validated, and tested directly on the scanned ECG images, without any manual feature extraction. Furthermore, a shallow neural network, a 1-D transformer classifier, and a 1-D CNN were trained, validated, and tested on ECG signals extracted from the aforementioned scanned images. Classification metrics were evaluated by means of sensitivity, specificity, positive and negative predictive values, accuracy, and area under the curve. Results prove that artificial intelligence can help clinicians in better stratifying risk of arrhythmia in patients with SQTS. In particular, shallow neural networks' processing features showed the best performance in identifying patients that will not suffer from a potentially lethal event. This could pave the way for refined ECG-based risk stratification in this group of patients, potentially helping in saving the lives of young and otherwise healthy individuals.
    MeSH term(s) Humans ; Artificial Intelligence ; Arrhythmias, Cardiac/diagnosis ; Arrhythmias, Cardiac/complications ; Neural Networks, Computer ; Electrocardiography/methods ; Death, Sudden, Cardiac/etiology
    Language English
    Publishing date 2023-11-01
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2052857-7
    ISSN 1424-8220 ; 1424-8220
    ISSN (online) 1424-8220
    ISSN 1424-8220
    DOI 10.3390/s23218900
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Rrm3 and Pif1 division of labor during replication through leading and lagging strand G-quadruplex.

    Varon, Mor / Dovrat, Daniel / Heuzé, Jonathan / Tsirkas, Ioannis / Singh, Saurabh P / Pasero, Philippe / Galletto, Roberto / Aharoni, Amir

    Nucleic acids research

    2023  Volume 52, Issue 4, Page(s) 1753–1762

    Abstract: Members of the conserved Pif1 family of 5'-3' DNA helicases can unwind G4s and mitigate their negative impact on genome stability. In Saccharomyces cerevisiae, two Pif1 family members, Pif1 and Rrm3, contribute to the suppression of genomic instability ... ...

    Abstract Members of the conserved Pif1 family of 5'-3' DNA helicases can unwind G4s and mitigate their negative impact on genome stability. In Saccharomyces cerevisiae, two Pif1 family members, Pif1 and Rrm3, contribute to the suppression of genomic instability at diverse regions including telomeres, centromeres and tRNA genes. While Pif1 can resolve lagging strand G4s in vivo, little is known regarding Rrm3 function at G4s and its cooperation with Pif1 for G4 replication. Here, we monitored replication through G4 sequences in real time to show that Rrm3 is essential for efficient replisome progression through G4s located on the leading strand template, but not on the lagging strand. We found that Rrm3 importance for replication through G4s is dependent on its catalytic activity and its N-terminal unstructured region. Overall, we show that Rrm3 and Pif1 exhibit a division of labor that enables robust replication fork progression through leading and lagging strand G4s, respectively.
    MeSH term(s) DNA Helicases/genetics ; DNA Helicases/metabolism ; DNA Replication/genetics ; G-Quadruplexes ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism
    Chemical Substances DNA Helicases (EC 3.6.4.-) ; Rrm3 protein, S cerevisiae (EC 3.6.1.-) ; Saccharomyces cerevisiae Proteins ; PIF1 protein, S cerevisiae (EC 3.6.1.-)
    Language English
    Publishing date 2023-12-20
    Publishing country England
    Document type Journal Article
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkad1205
    Database MEDical Literature Analysis and Retrieval System OnLINE

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