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• W4313348686 abstract "Abstract The long interspersed nuclear element-1 (LINE-1 or L1) retrotransposon is the only active autonomously replicating retrotransposon in the human genome. While most of the approximately 500,000 L1 copies are no longer able to propagate, those that retain activity can harm the cell by creating mutations, generating DNA damage, and triggering the expression of inflammatory factors such as the host interferon anti-viral response. Therefore, inhibition of L1 could be used to treat a variety of diseases associated with these processes. Previous research has focused on inhibition of the L1 reverse transcriptase (RT) activity, in part due to the prevalence of well-characterized existing inhibitors to related viral enzymes. Here we present the L1 endonuclease (EN) as an additional target for reducing the detrimental effects of L1 expression. We have screened and characterized a set of structurally diverse small molecule EN inhibitors using computational, biochemical, and cellular methods. We also show that these inhibitors reduce DNA damage created by L1 and inflammation reinforced by L1 activity in senescent cells. These inhibitors could be further used to modulate endogenous L1 function to better understand the lifecycle of this ubiquitous disease-relevant element." @default.
• W4313348686 created "2023-01-06" @default.
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• W4313348686 date "2022-12-29" @default.
• W4313348686 modified "2023-09-27" @default.
• W4313348686 title "Identification and characterization of small molecule inhibitors of the LINE-1 retrotransposon endonuclease" @default.
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• W4313348686 doi "https://doi.org/10.1101/2022.12.29.522256" @default.
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