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  1. Article ; Online: Mesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes.

    Sanchez, Ambrocio / Ortega, Pedro / Sakhtemani, Ramin / Manjunath, Lavanya / Oh, Sunwoo / Bournique, Elodie / Becker, Alexandrea / Kim, Kyumin / Durfee, Cameron / Temiz, Nuri Alpay / Chen, Xiaojiang S / Harris, Reuben S / Lawrence, Michael S / Buisson, Rémi

    Nature communications

    2024  Volume 15, Issue 1, Page(s) 2370

    Abstract: Antiviral DNA cytosine deaminases APOBEC3A and APOBEC3B are major sources of mutations in cancer by catalyzing cytosine-to-uracil deamination. APOBEC3A preferentially targets single-stranded DNAs, with a noted affinity for DNA regions that adopt stem- ... ...

    Abstract Antiviral DNA cytosine deaminases APOBEC3A and APOBEC3B are major sources of mutations in cancer by catalyzing cytosine-to-uracil deamination. APOBEC3A preferentially targets single-stranded DNAs, with a noted affinity for DNA regions that adopt stem-loop secondary structures. However, the detailed substrate preferences of APOBEC3A and APOBEC3B have not been fully established, and the specific influence of the DNA sequence on APOBEC3A and APOBEC3B deaminase activity remains to be investigated. Here, we find that APOBEC3B also selectively targets DNA stem-loop structures, and they are distinct from those subjected to deamination by APOBEC3A. We develop Oligo-seq, an in vitro sequencing-based method to identify specific sequence contexts promoting APOBEC3A and APOBEC3B activity. Through this approach, we demonstrate that APOBEC3A and APOBEC3B deaminase activity is strongly regulated by specific sequences surrounding the targeted cytosine. Moreover, we identify the structural features of APOBEC3B and APOBEC3A responsible for their substrate preferences. Importantly, we determine that APOBEC3B-induced mutations in hairpin-forming sequences within tumor genomes differ from the DNA stem-loop sequences mutated by APOBEC3A. Together, our study provides evidence that APOBEC3A and APOBEC3B can generate distinct mutation landscapes in cancer genomes, driven by their unique substrate selectivity.
    MeSH term(s) Humans ; Mutation ; Neoplasms/genetics ; Cytidine Deaminase/genetics ; Cytidine Deaminase/chemistry ; DNA ; Minor Histocompatibility Antigens/genetics ; Minor Histocompatibility Antigens/chemistry ; Cytosine ; Proteins
    Chemical Substances APOBEC3A protein, human (EC 3.5.4.5) ; Cytidine Deaminase (EC 3.5.4.5) ; DNA (9007-49-2) ; Minor Histocompatibility Antigens ; Cytosine (8J337D1HZY) ; APOBEC3B protein, human (EC 3.5.4.5) ; Proteins
    Language English
    Publishing date 2024-03-18
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-024-45909-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: APOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection.

    Manjunath, Lavanya / Oh, Sunwoo / Ortega, Pedro / Bouin, Alexis / Bournique, Elodie / Sanchez, Ambrocio / Martensen, Pia Møller / Auerbach, Ashley A / Becker, Jordan T / Seldin, Marcus / Harris, Reuben S / Semler, Bert L / Buisson, Rémi

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 820

    Abstract: Double-stranded RNA produced during viral replication and transcription activates both protein kinase R (PKR) and ribonuclease L (RNase L), which limits viral gene expression and replication through host shutoff of translation. In this study, we find ... ...

    Abstract Double-stranded RNA produced during viral replication and transcription activates both protein kinase R (PKR) and ribonuclease L (RNase L), which limits viral gene expression and replication through host shutoff of translation. In this study, we find that APOBEC3B forms a complex with PABPC1 to stimulate PKR and counterbalances the PKR-suppressing activity of ADAR1 in response to infection by many types of viruses. This leads to translational blockage and the formation of stress granules. Furthermore, we show that APOBEC3B localizes to stress granules through the interaction with PABPC1. APOBEC3B facilitates the formation of protein-RNA condensates with stress granule assembly factor (G3BP1) by protecting mRNA associated with stress granules from RNAse L-induced RNA cleavage during viral infection. These results not only reveal that APOBEC3B is a key regulator of different steps of the innate immune response throughout viral infection but also highlight an alternative mechanism by which APOBEC3B can impact virus replication without editing viral genomes.
    MeSH term(s) Humans ; Stress Granules ; DNA Helicases/metabolism ; RNA Helicases/metabolism ; Poly-ADP-Ribose Binding Proteins/metabolism ; RNA Recognition Motif Proteins/metabolism ; Virus Replication ; Virus Diseases ; Protein Kinases/metabolism ; eIF-2 Kinase/genetics ; eIF-2 Kinase/metabolism ; Cytoplasmic Granules/metabolism ; Cytidine Deaminase/genetics ; Cytidine Deaminase/metabolism ; Minor Histocompatibility Antigens/metabolism
    Chemical Substances DNA Helicases (EC 3.6.4.-) ; RNA Helicases (EC 3.6.4.13) ; Poly-ADP-Ribose Binding Proteins ; RNA Recognition Motif Proteins ; Protein Kinases (EC 2.7.-) ; eIF-2 Kinase (EC 2.7.11.1) ; G3BP1 protein, human (EC 3.6.4.12) ; APOBEC3B protein, human (EC 3.5.4.5) ; Cytidine Deaminase (EC 3.5.4.5) ; Minor Histocompatibility Antigens
    Language English
    Publishing date 2023-02-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-36445-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Order via subito

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  3. Article: Mesoscale DNA Features Impact APOBEC3A and APOBEC3B Deaminase Activity and Shape Tumor Mutational Landscapes.

    Sanchez, Ambrocio / Ortega, Pedro / Sakhtemani, Ramin / Manjunath, Lavanya / Oh, Sunwoo / Bournique, Elodie / Becker, Alexandrea / Kim, Kyumin / Durfee, Cameron / Temiz, Nuri Alpay / Chen, Xiaojiang S / Harris, Reuben S / Lawrence, Michael S / Buisson, Rémi

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Antiviral DNA cytosine deaminases APOBEC3A and APOBEC3B are major sources of mutations in cancer by catalyzing cytosine-to-uracil deamination. APOBEC3A preferentially targets singlestranded DNAs, with a noted affinity for DNA regions that adopt stem-loop ...

    Abstract Antiviral DNA cytosine deaminases APOBEC3A and APOBEC3B are major sources of mutations in cancer by catalyzing cytosine-to-uracil deamination. APOBEC3A preferentially targets singlestranded DNAs, with a noted affinity for DNA regions that adopt stem-loop secondary structures. However, the detailed substrate preferences of APOBEC3A and APOBEC3B have been fully established, and the specific influence of the DNA sequence on APOBEC3A APOBEC3B deaminase activity remains to be investigated. Here, we find that APOBEC3B selectively targets DNA stem-loop structures, and they are distinct from those subjected deamination by APOBEC3A. We develop Oligo-seq, a novel in vitro sequencing-based to identify specific sequence contexts promoting APOBEC3A and APOBEC3B activity. Through this approach, we demonstrate that APOBEC3A an APOBEC3B deaminase activity is strongly regulated by specific sequences surrounding the targeted cytosine. Moreover, we identify structural features of APOBEC3B and APOBEC3A responsible for their substrate preferences. Importantly, we determine that APOBEC3B-induced mutations in hairpin-forming sequences within tumor genomes differ from the DNA stem-loop sequences mutated by APOBEC3A. Together, our study provides evidence that APOBEC3A and APOBEC3B can generate mutation landscapes in cancer genomes, driven by their unique substrate selectivity.
    Language English
    Publishing date 2023-08-02
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.08.02.551499
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Genotoxic stress and viral infection induce transient expression of APOBEC3A and pro-inflammatory genes through two distinct pathways.

    Oh, Sunwoo / Bournique, Elodie / Bowen, Danae / Jalili, Pégah / Sanchez, Ambrocio / Ward, Ian / Dananberg, Alexandra / Manjunath, Lavanya / Tran, Genevieve P / Semler, Bert L / Maciejowski, John / Seldin, Marcus / Buisson, Rémi

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 4917

    Abstract: APOBEC3A is a cytidine deaminase driving mutagenesis in tumors. While APOBEC3A-induced mutations are common, APOBEC3A expression is rarely detected in cancer cells. This discrepancy suggests a tightly controlled process to regulate episodic APOBEC3A ... ...

    Abstract APOBEC3A is a cytidine deaminase driving mutagenesis in tumors. While APOBEC3A-induced mutations are common, APOBEC3A expression is rarely detected in cancer cells. This discrepancy suggests a tightly controlled process to regulate episodic APOBEC3A expression in tumors. In this study, we find that both viral infection and genotoxic stress transiently up-regulate APOBEC3A and pro-inflammatory genes using two distinct mechanisms. First, we demonstrate that STAT2 promotes APOBEC3A expression in response to foreign nucleic acid via a RIG-I, MAVS, IRF3, and IFN-mediated signaling pathway. Second, we show that DNA damage and DNA replication stress trigger a NF-κB (p65/IkBα)-dependent response to induce expression of APOBEC3A and other innate immune genes, independently of DNA or RNA sensing pattern recognition receptors and the IFN-signaling response. These results not only reveal the mechanisms by which tumors could episodically up-regulate APOBEC3A but also highlight an alternative route to stimulate the immune response after DNA damage independently of cGAS/STING or RIG-I/MAVS.
    MeSH term(s) Cell Line ; Cell Line, Tumor ; Cytidine Deaminase/genetics ; Cytidine Deaminase/metabolism ; DNA Damage ; Gene Expression Regulation ; Host-Pathogen Interactions ; Humans ; Immunity/genetics ; Proteins/genetics ; Proteins/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/physiology ; THP-1 Cells ; Transcription Factor RelA/metabolism ; Up-Regulation ; Viruses/growth & development
    Chemical Substances Proteins ; RNA, Messenger ; Transcription Factor RelA ; APOBEC3A protein, human (EC 3.5.4.5) ; Cytidine Deaminase (EC 3.5.4.5)
    Language English
    Publishing date 2021-08-13
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-25203-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

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