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Identification and characterization of small molecule inhibitors of the LINE-1 retrotransposon endonuclease

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  • Alexandra M. D’Ordine

    (Brown University
    Brown University)

  • Gerwald Jogl

    (Brown University
    Brown University)

  • John M. Sedivy

    (Brown University
    Brown University)

Abstract

The long interspersed nuclear element-1 (LINE-1 or L1) retrotransposon is the only active autonomously replicating retrotransposon in the human genome. L1 harms the cell by inserting new copies, generating DNA damage, and triggering inflammation. Therefore, L1 inhibition could be used to treat many diseases associated with these processes. Previous research has focused on inhibition of the L1 reverse transcriptase due to the prevalence of well-characterized inhibitors of related viral enzymes. Here we present the L1 endonuclease as another target for reducing L1 activity. We characterize structurally diverse small molecule endonuclease inhibitors using computational, biochemical, and biophysical methods. We also show that these inhibitors reduce L1 retrotransposition, L1-induced DNA damage, and inflammation reinforced by L1 in senescent cells. These inhibitors could be used for further pharmacological development and as tools to better understand the life cycle of this element and its impact on disease processes.

Suggested Citation

  • Alexandra M. D’Ordine & Gerwald Jogl & John M. Sedivy, 2024. "Identification and characterization of small molecule inhibitors of the LINE-1 retrotransposon endonuclease," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48066-x
    DOI: 10.1038/s41467-024-48066-x
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    1. Tammy A. Morrish & José Luis Garcia-Perez & Thomas D. Stamato & Guillermo E. Taccioli & JoAnn Sekiguchi & John V. Moran, 2007. "Endonuclease-independent LINE-1 retrotransposition at mammalian telomeres," Nature, Nature, vol. 446(7132), pages 208-212, March.
    2. Marco Cecco & Takahiro Ito & Anna P. Petrashen & Amy E. Elias & Nicholas J. Skvir & Steven W. Criscione & Alberto Caligiana & Greta Brocculi & Emily M. Adney & Jef D. Boeke & Oanh Le & Christian Beaus, 2019. "L1 drives IFN in senescent cells and promotes age-associated inflammation," Nature, Nature, vol. 566(7742), pages 73-78, February.
    3. Marco Cecco & Takahiro Ito & Anna P. Petrashen & Amy E. Elias & Nicholas J. Skvir & Steven W. Criscione & Alberto Caligiana & Greta Brocculi & Emily M. Adney & Jef D. Boeke & Oanh Le & Christian Beaus, 2019. "Author Correction: L1 drives IFN in senescent cells and promotes age-associated inflammation," Nature, Nature, vol. 572(7767), pages 5-5, August.
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