Long interspersed nuclear element-1 retrotransposon proteins (LINE-1) (LINE-1)

Long Interspersed Nuclear Element-1 (LINE-1 or L1) is a non-long terminal repeat (non-LTR) retrotransposon that constitutes approximately 17% of the human genome (Cordaux & Batzer, 2009, Nature Reviews Genetics). It encodes two essential proteins: ORF1p, a trimeric RNA-binding protein with chaperone activity (UniProt P12285), and ORF2p, which possesses endonuclease and reverse transcriptase activities (UniProt P12288). While most L1 elements are truncated or mutated, a small number of hot L1s remain retrotransposition-competent, capable of inserting new copies of themselves into the genome via an RNA intermediate (Hancks & Kazazian, 2016, Microbiology Spectrum). Dysregulation of LINE-1 is associated with genomic instability, DNA damage, and the activation of innate immune signaling pathways, such as the cGAS-STING pathway, due to the accumulation of cytoplasmic cDNA (De Cecco et al., 2019, Nature). Consequently, LINE-1 proteins have emerged as therapeutic targets in various cancers, where they are frequently overexpressed, and in neurodegenerative and autoimmune diseases (Ardeljan et al., 2017, Mobile DNA). Current therapeutic strategies primarily focus on inhibiting the ORF2p reverse transcriptase using nucleoside reverse transcriptase inhibitors (NRTIs) like Lamivudine or novel small molecules like TPN-101 to mitigate L1-driven inflammation and genomic damage (Lim et al., 2021, Nature Communications; Transposon Therapeutics).

Other names

L1L1RE1ORF1pORF2pLong interspersed element-1LINE1

Inhibition of ORF2p reverse transcriptase activity to prevent the synthesis of L1 cDNA, thereby reducing genomic integration and cytoplasmic DNA-mediated inflammatory signaling.