ArticleNucleic acids research2018
Missed cleavage opportunities by FEN1 lead to Okazaki fragment maturation via the long-flap pathway.
Article in Nucleic acids research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 42 citations in OpenAlex.
- Functional roles for FEN1 phosphate steering residues in multi-step substrate verification prior to reaction.The Journal of biological chemistry · 2026Article
- How DNA secondary structures drive replication fork instability.DNA repair · 2025Review
- Flap endonuclease-1 promotes pancreatic cancer progressionWorld journal of gastrointestinal oncology · 2025Article
- Nuclease-induced stepwise photodropping (NISP) to precisely investigate single-stranded DNA degradation behaviors of exonucleases and endonucleases.Nucleic acids research · 2024Article
- Protocol to study the direct binding of proteins to RNA:DNA hybrids or RNA-DNA chimeras in living cells using cross-linking immunoprecipitation.STAR protocols · 2024Article
- A scanning-to-incision switch in TFIIH-XPG induced by DNA damage licenses nucleotide excision repair.Nucleic acids research · 2023Article
- Mechanistic investigation of human maturation of Okazaki fragments reveals slow kinetics.Nature communications · 2022Article
- Flap endonuclease 1 Facilitated Hepatocellular Carcinoma Progression by Enhancing USP7/MDM2-mediated P53 Inactivation.International journal of biological sciences · 2022Article
- Heterogeneous nuclear ribonucleoprotein E1 binds polycytosine DNA and monitors genome integrity.Life science alliance · 2021Article
- Construction of a Three-Color Prism-Based TIRF Microscope to Study the Interactions and Dynamics of Macromolecules.Biology · 2021Article
- The role of IGF2BP2, an m6A reader gene, in human metabolic diseases and cancers.Cancer cell international · 2021Review
- Implementing fluorescence enhancement, quenching, and FRET for investigating flap endonuclease 1 enzymatic reaction at the single-molecule level.Computational and structural biotechnology journal · 2021Review
- Structure of the processive human Pol δ holoenzyme.Nature communications · 2020Article
- Review
- IGF2BP2 Promotes Liver Cancer Growth Through an m6A-FEN1-Dependent Mechanism.Frontiers in oncology · 2020Article
- Initial state of DNA-Dye complex sets the stage for protein induced fluorescence modulation.Nature communications · 2019Article
- Resolution of the Holliday junction recombination intermediate by human GEN1 at the single-molecule level.Nucleic acids research · 2019Article
- Human Exonuclease 1 (EXO1) Regulatory Functions in DNA Replication with Putative Roles in Cancer.International journal of molecular sciences · 2018Review
- Structural basis of 5' flap recognition and protein-protein interactions of human flap endonuclease 1.Nucleic acids research · 2018Article
- Positioning the 5'-flap junction in the active site controls the rate of flap endonuclease-1-catalyzed DNA cleavage.The Journal of biological chemistry · 2018Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
RNA-DNA hybrid primers synthesized by low fidelity DNA polymerase α to initiate eukaryotic lagging strand synthesis must be removed efficiently during Okazaki fragment (OF) maturation to complete DNA replication. In this process, each OF primer is displaced and the resulting 5'-single-stranded flap is cleaved by structure-specific 5'-nucleases, mainly Flap Endonuclease 1 (FEN1), to generate a ligatable nick. At least two models have been proposed to describe primer removal, namely short- and long-flap pathways that involve FEN1 or FEN1 along with Replication Protein A (RPA) and Dna2 helicase/nuclease, respectively. We addressed the question of pathway choice by studying the kinetic mechanism of FEN1 action on short- and long-flap DNA substrates. Using single molecule FRET and rapid quench-flow bulk cleavage assays, we showed that unlike short-flap substrates, which are bound, bent and cleaved within the first encounter between FEN1 and DNA, long-flap substrates can escape cleavage even after DNA binding and bending. Notably, FEN1 can access both substrates in the presence of RPA, but bending and cleavage of long-flap DNA is specifically inhibited. We propose that FEN1 attempts to process both short and long flaps, but occasional missed cleavage of the latter allows RPA binding and triggers the long-flap OF maturation pathway.
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Registered trials
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