BRCA1 and S phase DNA repair pathways restrict LINE-1 retrotransposition in human cells

Paolo Mita, Xiaoji Sun, David Fenyö, David J. Kahler, Donghui Li, Neta Agmon, Aleksandra Wudzinska, Sarah Keegan, Joel S. Bader, Chi Yun, Jef D. Boeke

    Research output: Contribution to journalArticle

    Abstract

    Long interspersed element-1 (LINE-1, or L1) is the only autonomous retrotransposon that is active in human cells. Different host factors have been shown to influence L1 mobility; however, systematic analyses of these factors are limited. Here, we developed a high-throughput microscopy-based retrotransposition assay that identified the double-stranded break (DSB) repair and Fanconi anemia (FA) factors active in the S/G2 phase as potent inhibitors and regulators of L1 activity. In particular, BRCA1, an E3 ubiquitin ligase with a key role in several DNA repair pathways, directly affects L1 retrotransposition frequency and structure and plays a distinct role in controlling L1 ORF2 protein translation through L1 mRNA binding. These results suggest the existence of a ‘battleground’ at the DNA replication fork between homologous recombination (HR) factors and L1 retrotransposons and reveal a potential role for L1 in the genotypic evolution of tumors characterized by BRCA1 and HR repair deficiencies.

    Original languageEnglish (US)
    Pages (from-to)179-191
    Number of pages13
    JournalNature Structural and Molecular Biology
    Volume27
    Issue number2
    DOIs
    StatePublished - Feb 1 2020

    ASJC Scopus subject areas

    • Structural Biology
    • Molecular Biology

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  • Cite this

    Mita, P., Sun, X., Fenyö, D., Kahler, D. J., Li, D., Agmon, N., Wudzinska, A., Keegan, S., Bader, J. S., Yun, C., & Boeke, J. D. (2020). BRCA1 and S phase DNA repair pathways restrict LINE-1 retrotransposition in human cells. Nature Structural and Molecular Biology, 27(2), 179-191. https://doi.org/10.1038/s41594-020-0374-z