ArticleThe Journal of biological chemistry2009
The 3'-flap pocket of human flap endonuclease 1 is critical for substrate binding and catalysis.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 61 citations in OpenAlex.
- Functional roles for FEN1 phosphate steering residues in multi-step substrate verification prior to reaction.The Journal of biological chemistry · 2026Article
- DNA polymerase I: structure, activity, and function in bacterial DNA replication and repair.Critical reviews in biochemistry and molecular biology · 2026Review
- EEPD1 evolved a unique DNA clamping dimer protecting reversed replication forks.Nucleic acids research · 2026Article
- Bacillus subtilis encodes a discrete flap endonuclease that cleaves RNA-DNA hybrids.PLoS genetics · 2023Article
- 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
- Recruiting Mechanism and Functional Role of a Third Metal Ion in the Enzymatic Activity of 5' Structure-Specific Nucleases.Journal of the American Chemical Society · 2020Article
- Structural basis of 5' flap recognition and protein-protein interactions of human flap endonuclease 1.Nucleic acids research · 2018Article
- A conserved loop-wedge motif moderates reaction site search and recognition by FEN1.Nucleic acids research · 2018Article
- Regional conformational flexibility couples substrate specificity and scissile phosphate diester selectivity in human flap endonuclease 1.Nucleic acids research · 2018Article
- Missed cleavage opportunities by FEN1 lead to Okazaki fragment maturation via the long-flap pathway.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
- Phosphate steering by Flap Endonuclease 1 promotes 5'-flap specificity and incision to prevent genome instability.Nature communications · 2017Article
- Single-molecule FRET unveils induced-fit mechanism for substrate selectivity in flap endonuclease 1.eLife · 2017Article
- Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression.EBioMedicine · 2016Article
- Cellularly active N-hydroxyurea FEN1 inhibitors block substrate entry to the active site.Nature chemical biology · 2016Article
- DNA and Protein Requirements for Substrate Conformational Changes Necessary for Human Flap Endonuclease-1-catalyzed Reaction.The Journal of biological chemistry · 2016Article
- Rate-determining Step of Flap Endonuclease 1 (FEN1) Reflects a Kinetic Bias against Long Flaps and Trinucleotide Repeat Sequences.The Journal of biological chemistry · 2015Article
- Okazaki fragment maturation involves α-segment error editing by the mammalian FEN1/MutSα functional complex.The EMBO journal · 2015Article
- Bending Forks and Wagging Dogs--It's about the DNA 3' Tail.Molecular cell · 2015Article
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
Flap endonuclease 1 (FEN1) proteins, which are present in all kingdoms of life, catalyze the sequence-independent hydrolysis of the bifurcated nucleic acid intermediates formed during DNA replication and repair. How FEN1s have evolved to preferentially cleave flap structures is of great interest especially in light of studies wherein mice carrying a catalytically deficient FEN1 were predisposed to cancer. Structural studies of FEN1s from phage to human have shown that, although they share similar folds, the FEN1s of higher organisms contain a 3'-extrahelical nucleotide (3'-flap) binding pocket. When presented with 5'-flap substrates having a 3'-flap, archaeal and eukaryotic FEN1s display enhanced reaction rates and cleavage site specificity. To investigate the role of this interaction, a kinetic study of human FEN1 (hFEN1) employing well defined DNA substrates was conducted. The presence of a 3'-flap on substrates reduced Km and increased multiple- and single turnover rates of endonucleolytic hydrolysis at near physiological salt concentrations. Exonucleolytic and fork-gap-endonucleolytic reactions were also stimulated by the presence of a 3'-flap, and the absence of a 3'-flap from a 5'-flap substrate was more detrimental to hFEN1 activity than removal of the 5'-flap or introduction of a hairpin into the 5'-flap structure. hFEN1 reactions were predominantly rate-limited by product release regardless of the presence or absence of a 3'-flap. Furthermore, the identity of the stable enzyme product species was deduced from inhibition studies to be the 5'-phosphorylated product. Together the results indicate that the presence of a 3'-flap is the critical feature for efficient hFEN1 substrate recognition and catalysis.
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