Genomic alteration is a driving force in evolution; however, it also poses 20 μm25ISG networkMOV10Merge (+DAPI)EIF3DLARP1SART3PATL1TFAP2BXRN1V1XRN2DDX60LADARB1MOV10APOBEC3BZC3HAHPSEMKI67TRIM25LGALS3BPHELZ2OASLDDX60ADAREIF2AK2ELAVL1HERC5IFIT1DHX58IFIT2IFI16WTAPIFIT3ARP12PTRIM56GNA12CENPVPEG10ARHGEF2FYNJUPRBBP6BAZ1ADNA2L1 ORF1pISG proteinSMARCA1FMNL2TOP2AL1 +controlELAVL2CKAP2LIGF2BP3IGF2BP2S100PMYH10L1 +HELZ2HNRNPMRTCBSSBPLOD2NPM1SSR1GPATCHRRP8ZFP36L2FGL2L1 +OASLAFF1CMSS1AHNAKSLC3A2LTFELL2FSCN1L1 +TFRCa threat to genomic integrity, which may cause disease-associated muta-tions. Transposable elements (TEs) are mobile genetic elements that move to new genomic locations via DNA (i.e., DNA transposons) or RNA intermediates (i.e., retrotransposons). Human retrotransposons, Long INterspersed Element-1s (LINE-1s or L1s) and Short INterspersed Elements (SINEs), represent ap-proximately 17% and 11% of the genome, respectively, and are still frequently “jumping” in our genome. De novo L1 and SINE insertions, called retrotranspo-sition, are responsible for sporadic genetic diseases, including various types of cancer, but their mechanisms of action are still largely unknown. We believe that elucidating the mechanisms of retrotransposition is crucial to understanding the processes that lead to human diseases, genetic variation, and genome evolution.We are currently focused on i) exploring the mechanisms of L1/SINE ret-rotransposition and ii) examining the impact of L1/SINE expression on disease-related phenotypes such as chronic inflammation. Because L1/SINE may have been co-evolving within the host genomes for more than millions of years, host cellular proteins likely regulate these mobile genetic elements through direct interaction with their RNA and proteins. We undertook a proteomic analysis of L1-encoded proteins to identify host factors that regulate L1 retrotransposition and found that numerous innate immune response factors such as Interferon-Stimulated Gene (ISG) products, as well as DNA repair proteins, form a com-plex with L1. Several identified ISG factors significantly inhibit retrotranspo-sons; in particular, we found that the RNA helicase HELZ2 specifically degrades L1 RNA and suppresses the L1-induced innate immune response. This suggests that host cells use a system similar to their defense mechanism against viruses to suppress genomic alterations induced by retrotransposons.We will continue to elucidate the mechanisms of L1 and SINE retrotranspo-sition by elucidating the function of host factors that regulate these elements. This will lead to the development of new methods to inhibit retrotransposon activities.Figure: Interferon Stimulated Gene (ISG) factors interact with L1 and suppress cytoplasmic L1 accumulation(Left) Host factors interacting with L1 identified by mass spectrometry. These include a network of ISG-derived proteins.(Right) The ISG factors HELZ2 and OASL inhibit L1 ret-rotransposition at different steps of its replication cycle. While HELZ2 degrades L1 RNA and inhibits the cytoplas-mic accumulation of the L1 complex, OASL perturbs its localization. MOV10, a well-known L1 inhibitor, served as a positive control. (Data modified from Luqman-Fatah A. et al., Nature Communications. 14, 203. (2023))Recent Major PublicationsHara T, Nakaoka H, Miyoshi T, Ishikawa F. The CST com-plex facilitates cell survival under oxidative genotoxic stress. PLOS ONE 18, e0289304. (2023)Luqman-Fatah A, Miyoshi T. Human LINE-1 Retrotrans-posons: Impacts on the Genome and Regulation by Host Factors. Genes Genet Syst 98, 121-154. (2023)Luqman-Fatah A, Watanabe Y, Uno K, Ishikawa F, Moran JV, Miyoshi T. The interferon stimulated gene-encoded protein HELZ2 1 inhibits human LINE-1 retrotransposi-tion and LINE-1 RNA-mediated type I interferon induc-tion. Nature Communnications 14, 203. (2023)Invited presentationsMiyoshi T. “A network of interferon-stimulated genes inhibits human LINE-1 retrotransposition” EMBL Sym-posium: The Mobile Genome: Genetic and Physiological Impacts of Transposable Elements. (Heidelberg, Ger-many) November 2023Laboratory for Retrotransposon DynamicsTeam Leader: Tomoichiro Miyoshi
元のページ ../index.html#31