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  1. Artikel ; Online: Telomeres as hotspots for innate immunity and inflammation.

    Nassour, Joe / Przetocka, Sara / Karlseder, Jan

    DNA repair

    2023  Band 133, Seite(n) 103591

    Abstract: Aging is marked by the gradual accumulation of deleterious changes that disrupt organ function, creating an altered physiological state that is permissive for the onset of prevalent human diseases. While the exact mechanisms governing aging remain a ... ...

    Abstract Aging is marked by the gradual accumulation of deleterious changes that disrupt organ function, creating an altered physiological state that is permissive for the onset of prevalent human diseases. While the exact mechanisms governing aging remain a subject of ongoing research, there are several cellular and molecular hallmarks that contribute to this biological process. This review focuses on two factors, namely telomere dysfunction and inflammation, which have emerged as crucial contributors to the aging process. We aim to discuss the mechanistic connections between these two distinct hallmarks and provide compelling evidence highlighting the loss of telomere protection as a driver of pro-inflammatory states associated with aging. By reevaluating the interplay between telomeres, innate immunity, and inflammation, we present novel perspectives on the etiology of aging and its associated diseases.
    Mesh-Begriff(e) Humans ; Aging/genetics ; Telomere ; Inflammation ; Immunity, Innate ; Cellular Senescence
    Sprache Englisch
    Erscheinungsdatum 2023-11-05
    Erscheinungsland Netherlands
    Dokumenttyp Review ; Journal Article
    ZDB-ID 2071608-4
    ISSN 1568-7856 ; 1568-7864
    ISSN (online) 1568-7856
    ISSN 1568-7864
    DOI 10.1016/j.dnarep.2023.103591
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis.

    Nassour, Joe / Aguiar, Lucia Gutierrez / Correia, Adriana / Schmidt, Tobias T / Mainz, Laura / Przetocka, Sara / Haggblom, Candy / Tadepalle, Nimesha / Williams, April / Shokhirev, Maxim N / Akincilar, Semih C / Tergaonkar, Vinay / Shadel, Gerald S / Karlseder, Jan

    Nature

    2023  Band 614, Heft 7949, Seite(n) 767–773

    Abstract: Cancers arise through the accumulation of genetic and epigenetic alterations that enable cells to evade telomere-based proliferative barriers and achieve immortality. One such barrier is replicative crisis-an autophagy-dependent program that eliminates ... ...

    Abstract Cancers arise through the accumulation of genetic and epigenetic alterations that enable cells to evade telomere-based proliferative barriers and achieve immortality. One such barrier is replicative crisis-an autophagy-dependent program that eliminates checkpoint-deficient cells with unstable telomeres and other cancer-relevant chromosomal aberrations
    Mesh-Begriff(e) Humans ; DNA/biosynthesis ; DNA/genetics ; DNA/metabolism ; DNA Replication ; Mitochondria/genetics ; Mitochondria/metabolism ; Neoplasms/genetics ; Neoplasms/pathology ; RNA, Long Noncoding/biosynthesis ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; Telomere/genetics ; Telomere/metabolism ; Interferons ; Immunity, Innate ; Autophagy ; Signal Transduction
    Chemische Substanzen DNA (9007-49-2) ; RNA, Long Noncoding ; ZBP1 protein, human ; cGAS protein, human (EC 2.7.7.-) ; MAVS protein, human ; Interferons (9008-11-1) ; STING1 protein, human
    Sprache Englisch
    Erscheinungsdatum 2023-02-08
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-023-05710-8
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: RNAi Screening Uncovers a Synthetic Sick Interaction between CtIP and the BARD1 Tumor Suppressor.

    Bolck, Hella A / Przetocka, Sara / Meier, Roger / von Aesch, Christine / Zurfluh, Christina / Hänggi, Kay / Spegg, Vincent / Altmeyer, Matthias / Stebler, Michael / Nørrelykke, Simon F / Horvath, Peter / Sartori, Alessandro A / Porro, Antonio

    Cells

    2022  Band 11, Heft 4

    Abstract: Human CtIP is best known for its role in DNA end resection to initiate DNA double-strand break repair by homologous recombination. Recently, CtIP has also been shown to protect reversed replication forks from nucleolytic degradation upon DNA replication ... ...

    Abstract Human CtIP is best known for its role in DNA end resection to initiate DNA double-strand break repair by homologous recombination. Recently, CtIP has also been shown to protect reversed replication forks from nucleolytic degradation upon DNA replication stress. However, still little is known about the DNA damage response (DDR) networks that preserve genome integrity and sustain cell survival in the context of CtIP insufficiency. Here, to reveal such potential buffering relationships, we screened a DDR siRNA library in CtIP-deficient cells to identify candidate genes that induce synthetic sickness/lethality (SSL). Our analyses unveil a negative genetic interaction between CtIP and BARD1, the heterodimeric binding partner of BRCA1. We found that simultaneous disruption of CtIP and BARD1 triggers enhanced apoptosis due to persistent replication stress-induced DNA lesions giving rise to chromosomal abnormalities. Moreover, we observed that the genetic interaction between CtIP and BARD1 occurs independently of the BRCA1-BARD1 complex formation and might be, therefore, therapeutical relevant for the treatment of BRCA-defective tumors.
    Mesh-Begriff(e) DNA Breaks, Double-Stranded ; DNA Repair ; Endodeoxyribonucleases/genetics ; Endodeoxyribonucleases/metabolism ; Genes, Tumor Suppressor ; Homologous Recombination ; Humans ; RNA Interference ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism
    Chemische Substanzen Tumor Suppressor Proteins ; BARD1 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Endodeoxyribonucleases (EC 3.1.-) ; RBBP8 protein, human (EC 3.1.-)
    Sprache Englisch
    Erscheinungsdatum 2022-02-12
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells11040643
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: A stapled peptide mimetic of the CtIP tetramerization motif interferes with double-strand break repair and replication fork protection.

    Kuster, Anika / Mozaffari, Nour L / Wilkinson, Oliver J / Wojtaszek, Jessica L / Zurfluh, Christina / Przetocka, Sara / Zyla, Dawid / von Aesch, Christine / Dillingham, Mark S / Williams, R Scott / Sartori, Alessandro A

    Science advances

    2021  Band 7, Heft 8

    Abstract: Cancer cells display high levels of DNA damage and replication stress, vulnerabilities that could be exploited by drugs targeting DNA repair proteins. Human CtIP promotes homology-mediated repair of DNA double-strand breaks (DSBs) and protects stalled ... ...

    Abstract Cancer cells display high levels of DNA damage and replication stress, vulnerabilities that could be exploited by drugs targeting DNA repair proteins. Human CtIP promotes homology-mediated repair of DNA double-strand breaks (DSBs) and protects stalled replication forks from nucleolytic degradation, thus representing an attractive candidate for targeted cancer therapy. Here, we establish a peptide mimetic of the CtIP tetramerization motif that inhibits CtIP activity. The hydrocarbon-stapled peptide encompassing amino acid residues 18 to 28 of CtIP (SP
    Sprache Englisch
    Erscheinungsdatum 2021-02-19
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.abc6381
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours.

    Dibitetto, Diego / Liptay, Martin / Vivalda, Francesca / Dogan, Hülya / Gogola, Ewa / González Fernández, Martín / Duarte, Alexandra / Schmid, Jonas A / Decollogny, Morgane / Francica, Paola / Przetocka, Sara / Durant, Stephen T / Forment, Josep V / Klebic, Ismar / Siffert, Myriam / de Bruijn, Roebi / Kousholt, Arne N / Marti, Nicole A / Dettwiler, Martina /
    Sørensen, Claus S / Tille, Jean-Christophe / Undurraga, Manuela / Labidi-Galy, Intidhar / Lopes, Massimo / Sartori, Alessandro A / Jonkers, Jos / Rottenberg, Sven

    Nature communications

    2024  Band 15, Heft 1, Seite(n) 4430

    Abstract: Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA ... ...

    Abstract Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA1. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours, we identify a function for γH2AX in orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-driven replication fork degradation is elicited by suppressing CtIP-mediated fork protection. As a result, H2AX loss restores replication fork stability and increases chemoresistance in BRCA1/2-deficient tumour cells without restoring homology-directed DNA repair, as highlighted by the lack of DNA damage-induced RAD51 foci. Furthermore, in the attempt to discover acquired genetic vulnerabilities, we find that ATM but not ATR inhibition overcomes PARP inhibitor (PARPi) resistance in H2AX-deficient tumours by interfering with CtIP-mediated fork protection. In summary, our results demonstrate a role for H2AX in replication fork biology in BRCA-deficient tumours and establish a function of H2AX separable from its classical role in DNA damage signalling and DSB repair.
    Mesh-Begriff(e) Animals ; Female ; Humans ; Mice ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Ataxia Telangiectasia Mutated Proteins/genetics ; BRCA1 Protein/metabolism ; BRCA1 Protein/deficiency ; BRCA1 Protein/genetics ; BRCA2 Protein/metabolism ; BRCA2 Protein/genetics ; BRCA2 Protein/deficiency ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Breast Neoplasms/drug therapy ; Carrier Proteins/metabolism ; Carrier Proteins/genetics ; Cell Line, Tumor ; DNA Breaks, Double-Stranded ; DNA Damage ; DNA Repair ; DNA Replication/drug effects ; Drug Resistance, Neoplasm/genetics ; Histones/metabolism ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Rad51 Recombinase/metabolism ; Rad51 Recombinase/genetics ; Tumor Suppressor p53-Binding Protein 1/metabolism ; Tumor Suppressor p53-Binding Protein 1/genetics ; Mice, Nude
    Chemische Substanzen Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; ATR protein, human (EC 2.7.11.1) ; BRCA1 Protein ; BRCA1 protein, human ; BRCA2 Protein ; BRCA2 protein, human ; Carrier Proteins ; H2AX protein, human ; Histones ; Poly(ADP-ribose) Polymerase Inhibitors ; Rad51 Recombinase (EC 2.7.7.-) ; TP53BP1 protein, human ; Tumor Suppressor p53-Binding Protein 1
    Sprache Englisch
    Erscheinungsdatum 2024-05-24
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-024-48715-1
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel ; Online: CtIP-Mediated Fork Protection Synergizes with BRCA1 to Suppress Genomic Instability upon DNA Replication Stress.

    Przetocka, Sara / Porro, Antonio / Bolck, Hella A / Walker, Christina / Lezaja, Aleksandra / Trenner, Anika / von Aesch, Christine / Himmels, Sarah-Felicitas / D'Andrea, Alan D / Ceccaldi, Raphael / Altmeyer, Matthias / Sartori, Alessandro A

    Molecular cell

    2018  Band 72, Heft 3, Seite(n) 568–582.e6

    Abstract: Protecting stalled DNA replication forks from degradation by promiscuous nucleases is essential to prevent genomic instability, a major driving force of tumorigenesis. Several proteins commonly associated with the repair of DNA double-strand breaks (DSBs) ...

    Abstract Protecting stalled DNA replication forks from degradation by promiscuous nucleases is essential to prevent genomic instability, a major driving force of tumorigenesis. Several proteins commonly associated with the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) have been implicated in the stabilization of stalled forks. Human CtIP, in conjunction with the MRE11 nuclease complex, plays an important role in HR by promoting DSB resection. Here, we report an unanticipated function for CtIP in protecting reversed forks from degradation. Unlike BRCA proteins, which defend nascent DNA strands from nucleolytic attack by MRE11, we find that CtIP protects perturbed forks from erroneous over-resection by DNA2. Finally, we uncover functionally synergistic effects between CtIP and BRCA1 in mitigating replication-stress-induced genomic instability. Collectively, our findings reveal a DSB-resection- and MRE11-independent role for CtIP in preserving fork integrity that contributes to the survival of BRCA1-deficient cells.
    Mesh-Begriff(e) BRCA1 Protein ; BRCA2 Protein ; Carrier Proteins/metabolism ; Carrier Proteins/physiology ; Cell Line ; DNA Breaks, Double-Stranded ; DNA Helicases/physiology ; DNA Repair ; DNA Replication/physiology ; DNA-Binding Proteins ; Deoxyribonucleases ; Genomic Instability/physiology ; Homologous Recombination/genetics ; Humans ; MRE11 Homologue Protein/metabolism ; Nuclear Proteins/metabolism ; Nuclear Proteins/physiology ; Protein Binding
    Chemische Substanzen BRCA1 Protein ; BRCA1 protein, human ; BRCA2 Protein ; Carrier Proteins ; DNA-Binding Proteins ; MRE11 protein, human ; Nuclear Proteins ; Deoxyribonucleases (EC 3.1.-) ; MRE11 Homologue Protein (EC 3.1.-) ; RBBP8 protein, human (EC 3.1.-) ; DNA Helicases (EC 3.6.4.-) ; DNA2 protein, human (EC 3.6.4.12)
    Sprache Englisch
    Erscheinungsdatum 2018-10-18
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2018.09.014
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel ; Online: Structure of the Complex of Human Programmed Death 1, PD-1, and Its Ligand PD-L1.

    Zak, Krzysztof M / Kitel, Radoslaw / Przetocka, Sara / Golik, Przemyslaw / Guzik, Katarzyna / Musielak, Bogdan / Dömling, Alexander / Dubin, Grzegorz / Holak, Tad A

    Structure (London, England : 1993)

    2015  Band 23, Heft 12, Seite(n) 2341–2348

    Abstract: Targeting the PD-1/PD-L1 immunologic checkpoint with monoclonal antibodies has recently provided breakthrough progress in the treatment of melanoma, non-small cell lung cancer, and other types of cancer. Small-molecule drugs interfering with this pathway ...

    Abstract Targeting the PD-1/PD-L1 immunologic checkpoint with monoclonal antibodies has recently provided breakthrough progress in the treatment of melanoma, non-small cell lung cancer, and other types of cancer. Small-molecule drugs interfering with this pathway are highly awaited, but their development is hindered by insufficient structural information. This study reveals the molecular details of the human PD-1/PD-L1 interaction based on an X-ray structure of the complex. First, it is shown that the ligand binding to human PD-1 is associated with significant plasticity within the receptor. Second, a detailed molecular map of the interaction surface is provided, allowing definition of the regions within both interacting partners that may likely be targeted by small molecules.
    Mesh-Begriff(e) Amino Acid Sequence ; B7-H1 Antigen/chemistry ; B7-H1 Antigen/metabolism ; Binding Sites ; Humans ; Molecular Sequence Data ; Programmed Cell Death 1 Receptor/chemistry ; Programmed Cell Death 1 Receptor/metabolism ; Protein Binding
    Chemische Substanzen B7-H1 Antigen ; Programmed Cell Death 1 Receptor
    Sprache Englisch
    Erscheinungsdatum 2015-12-01
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1213087-4
    ISSN 1878-4186 ; 0969-2126
    ISSN (online) 1878-4186
    ISSN 0969-2126
    DOI 10.1016/j.str.2015.09.010
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