ArticleNucleic acids research2021
Structural dissection of sequence recognition and catalytic mechanism of human LINE-1 endonuclease.
Article in Nucleic acids research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 13 citations in OpenAlex.
- LINE-1 Epigenetic Repression and Regulation of Immunity.Viruses · 2026Review
- Structural and biochemical studies of mobile retrotransposon proteins in action.Current opinion in structural biology · 2025Review
- Structural mechanism of LINE-1 target-primed reverse transcription.Science (New York, N.Y.) · 2025Article
- Diverse single-stranded nucleic acid binding proteins enable both stable protection and rapid exchange required for biological function.QRB discovery · 2025Article
- Domain Mobility in the ORF2p Complex Revealed by Molecular Dynamics Simulations and Big Data Analysis.International journal of molecular sciences · 2024Article
- L1-ORF1p nucleoprotein can rapidly assume distinct conformations and simultaneously bind more than one nucleic acid.Nucleic acids research · 2024Article
- Identification and characterization of small molecule inhibitors of the LINE-1 retrotransposon endonuclease.Nature communications · 2024Article
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- Structure of the R2 non-LTR retrotransposon initiating target-primed reverse transcription.Science (New York, N.Y.) · 2023Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Long interspersed nuclear element-1 (L1) is an autonomous non-LTR retrotransposon comprising ∼20% of the human genome. L1 self-propagation causes genomic instability and is strongly associated with aging, cancer and other diseases. The endonuclease domain of L1's ORFp2 protein (L1-EN) initiates de novo L1 integration by nicking the consensus sequence 5'-TTTTT/AA-3'. In contrast, related nucleases including structurally conserved apurinic/apyrimidinic endonuclease 1 (APE1) are non-sequence specific. To investigate mechanisms underlying sequence recognition and catalysis by L1-EN, we solved crystal structures of L1-EN complexed with DNA substrates. This showed that conformational properties of the preferred sequence drive L1-EN's sequence-specificity and catalysis. Unlike APE1, L1-EN does not bend the DNA helix, but rather causes 'compression' near the cleavage site. This provides multiple advantages for L1-EN's role in retrotransposition including facilitating use of the nicked poly-T DNA strand as a primer for reverse transcription. We also observed two alternative conformations of the scissile bond phosphate, which allowed us to model distinct conformations for a nucleophilic attack and a transition state that are likely applicable to the entire family of nucleases. This work adds to our mechanistic understanding of L1-EN and related nucleases and should facilitate development of L1-EN inhibitors as potential anticancer and antiaging therapeutics.
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