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  1. Artikel ; Online: R-Loop Immunoprecipitation: A Method to Detect R-Loop Interacting Factors.

    Beghè, Chiara / Gromak, Natalia

    Methods in molecular biology (Clifton, N.J.)

    2021  Band 2528, Seite(n) 215–237

    Abstract: R-loops are non-B-DNA structures consisting of an RNA/DNA hybrid and a displaced single-stranded DNA. They arise during transcription and play important biological roles. However, perturbation of R-loop levels represents a source of DNA damage and genome ...

    Abstract R-loops are non-B-DNA structures consisting of an RNA/DNA hybrid and a displaced single-stranded DNA. They arise during transcription and play important biological roles. However, perturbation of R-loop levels represents a source of DNA damage and genome instability resulting in human diseases, including cancer and neurodegeneration. In this chapter, we describe a protocol which allows detection of R-loop interactors using affinity purification with S9.6 antibody, specific for RNA/DNA hybrids, followed by Western blotting or mass spectrometry. Multiple specificity controls including addition of synthetic competitors and RNase H treatment are described to verify the specificity of identified R-loop-binding factors. The identification of new R-loop interacting factors and the characterization of their involvement in R-loop biology provides a powerful resource to study the role of these important structures in health and disease.
    Mesh-Begriff(e) DNA/genetics ; Genomic Instability ; Humans ; Immunoprecipitation ; R-Loop Structures ; RNA/genetics ; Ribonuclease H/chemistry
    Chemische Substanzen RNA (63231-63-0) ; DNA (9007-49-2) ; Ribonuclease H (EC 3.1.26.4)
    Sprache Englisch
    Erscheinungsdatum 2021-05-14
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-2477-7_14
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Hypoxia-induced transcriptional stress is mediated by ROS-induced R-loops.

    Ma, Tiffany S / Worth, Katja R / Maher, Conor / Ng, Natalie / Beghè, Chiara / Gromak, Natalia / Rose, Anna M / Hammond, Ester M

    Nucleic acids research

    2023  Band 51, Heft 21, Seite(n) 11584–11599

    Abstract: Hypoxia is a common feature of solid tumors and is associated with poor patient prognosis, therapy resistance and metastasis. Radiobiological hypoxia (<0.1% O2) is one of the few physiologically relevant stresses that activates both the replication ... ...

    Abstract Hypoxia is a common feature of solid tumors and is associated with poor patient prognosis, therapy resistance and metastasis. Radiobiological hypoxia (<0.1% O2) is one of the few physiologically relevant stresses that activates both the replication stress/DNA damage response and the unfolded protein response. Recently, we found that hypoxia also leads to the robust accumulation of R-loops, which led us to question here both the mechanism and consequence of hypoxia-induced R-loops. Interestingly, we found that the mechanism of R-loop accumulation in hypoxia is dependent on non-DNA damaging levels of reactive oxygen species. We show that hypoxia-induced R-loops play a critical role in the transcriptional stress response, evidenced by the repression of ribosomal RNA synthesis and the translocation of nucleolin from the nucleolus into the nucleoplasm. Upon depletion of R-loops, we observed a rescue of both rRNA transcription and nucleolin translocation in hypoxia. Mechanistically, R-loops accumulate on the rDNA in hypoxia and promote the deposition of heterochromatic H3K9me2 which leads to the inhibition of Pol I-mediated transcription of rRNA. These data highlight a novel mechanistic insight into the hypoxia-induced transcriptional stress response through the ROS-R-loop-H3K9me2 axis. Overall, this study highlights the contribution of transcriptional stress to hypoxia-mediated tumorigenesis.
    Mesh-Begriff(e) Humans ; DNA, Ribosomal/genetics ; DNA, Ribosomal/metabolism ; R-Loop Structures ; Reactive Oxygen Species/metabolism ; RNA Polymerase I/metabolism ; Transcription, Genetic ; Tumor Hypoxia
    Chemische Substanzen DNA, Ribosomal ; Reactive Oxygen Species ; RNA Polymerase I (EC 2.7.7.6)
    Sprache Englisch
    Erscheinungsdatum 2023-10-16
    Erscheinungsland England
    Dokumenttyp 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/gkad858
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: APOBEC3B regulates R-loops and promotes transcription-associated mutagenesis in cancer.

    McCann, Jennifer L / Cristini, Agnese / Law, Emily K / Lee, Seo Yun / Tellier, Michael / Carpenter, Michael A / Beghè, Chiara / Kim, Jae Jin / Sanchez, Anthony / Jarvis, Matthew C / Stefanovska, Bojana / Temiz, Nuri A / Bergstrom, Erik N / Salamango, Daniel J / Brown, Margaret R / Murphy, Shona / Alexandrov, Ludmil B / Miller, Kyle M / Gromak, Natalia /
    Harris, Reuben S

    Nature genetics

    2023  Band 55, Heft 10, Seite(n) 1721–1734

    Abstract: The single-stranded DNA cytosine-to-uracil deaminase APOBEC3B is an antiviral protein implicated in cancer. However, its substrates in cells are not fully delineated. Here APOBEC3B proteomics reveal interactions with a surprising number of R-loop factors. ...

    Abstract The single-stranded DNA cytosine-to-uracil deaminase APOBEC3B is an antiviral protein implicated in cancer. However, its substrates in cells are not fully delineated. Here APOBEC3B proteomics reveal interactions with a surprising number of R-loop factors. Biochemical experiments show APOBEC3B binding to R-loops in cells and in vitro. Genetic experiments demonstrate R-loop increases in cells lacking APOBEC3B and decreases in cells overexpressing APOBEC3B. Genome-wide analyses show major changes in the overall landscape of physiological and stimulus-induced R-loops with thousands of differentially altered regions, as well as binding of APOBEC3B to many of these sites. APOBEC3 mutagenesis impacts genes overexpressed in tumors and splice factor mutant tumors preferentially, and APOBEC3-attributed kataegis are enriched in RTCW motifs consistent with APOBEC3B deamination. Taken together with the fact that APOBEC3B binds single-stranded DNA and RNA and preferentially deaminates DNA, these results support a mechanism in which APOBEC3B regulates R-loops and contributes to R-loop mutagenesis in cancer.
    Mesh-Begriff(e) Humans ; R-Loop Structures ; DNA, Single-Stranded/genetics ; Genome-Wide Association Study ; Mutagenesis ; Neoplasms/genetics ; Neoplasms/pathology ; Cytidine Deaminase/genetics ; Minor Histocompatibility Antigens/genetics ; Minor Histocompatibility Antigens/metabolism
    Chemische Substanzen DNA, Single-Stranded ; Cytidine Deaminase (EC 3.5.4.5) ; Minor Histocompatibility Antigens ; APOBEC3B protein, human (EC 3.5.4.5)
    Sprache Englisch
    Erscheinungsdatum 2023-09-21
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/s41588-023-01504-w
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes.

    Giordano, Anna Maria Sole / Luciani, Marco / Gatto, Francesca / Abou Alezz, Monah / Beghè, Chiara / Della Volpe, Lucrezia / Migliara, Alessandro / Valsoni, Sara / Genua, Marco / Dzieciatkowska, Monika / Frati, Giacomo / Tahraoui-Bories, Julie / Giliani, Silvia Clara / Orcesi, Simona / Fazzi, Elisa / Ostuni, Renato / D'Alessandro, Angelo / Di Micco, Raffaella / Merelli, Ivan /
    Lombardo, Angelo / Reijns, Martin A M / Gromak, Natalia / Gritti, Angela / Kajaste-Rudnitski, Anna

    The Journal of experimental medicine

    2022  Band 219, Heft 4

    Abstract: Aberrant induction of type I IFN is a hallmark of the inherited encephalopathy Aicardi-Goutières syndrome (AGS), but the mechanisms triggering disease in the human central nervous system (CNS) remain elusive. Here, we generated human models of AGS using ... ...

    Abstract Aberrant induction of type I IFN is a hallmark of the inherited encephalopathy Aicardi-Goutières syndrome (AGS), but the mechanisms triggering disease in the human central nervous system (CNS) remain elusive. Here, we generated human models of AGS using genetically modified and patient-derived pluripotent stem cells harboring TREX1 or RNASEH2B loss-of-function alleles. Genome-wide transcriptomic analysis reveals that spontaneous proinflammatory activation in AGS astrocytes initiates signaling cascades impacting multiple CNS cell subsets analyzed at the single-cell level. We identify accumulating DNA damage, with elevated R-loop and micronuclei formation, as a driver of STING- and NLRP3-related inflammatory responses leading to the secretion of neurotoxic mediators. Importantly, pharmacological inhibition of proapoptotic or inflammatory cascades in AGS astrocytes prevents neurotoxicity without apparent impact on their increased type I IFN responses. Together, our work identifies DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes, suggests a role for AGS gene products in R-loop homeostasis, and identifies common denominators of disease that can be targeted to prevent astrocyte-mediated neurotoxicity in AGS.
    Mesh-Begriff(e) Astrocytes/metabolism ; Autoimmune Diseases of the Nervous System/genetics ; DNA Damage ; Humans ; Inflammation/genetics ; Inflammation/metabolism ; Nervous System Malformations/genetics
    Sprache Englisch
    Erscheinungsdatum 2022-03-09
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20211121
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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