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Structural basis of 5' flap recognition and protein-protein interactions of human flap endonuclease 1.

Xu H, Shi R, Han W, Cheng J, Xu X, Cheng K, Wang L, Tian B, Zheng L, Shen B, Hua Y, Zhao Y
Nucleic Acids Res 46 11315-11325 (2018)
Related entries: 5zoe, 5zof, 5zog

Cited: 10 times
EuropePMC logo PMID: 30295841

Abstract

Human flap endonuclease 1 (hFEN1) is a structure-specific nuclease essential for DNA replication and repair processes. hFEN1 has 5' flap removal activity, as well as gap endonuclease activity that is critical for restarting stalled replication forks. Here, we report the crystal structures of wild-type and mutant hFEN1 proteins in complex with DNA substrates, followed by mutagenesis studies that provide mechanistic insight into the protein-protein interactions of hFEN1. We found that in an α-helix forming the helical gateway of hFEN1 recognizes the 5' flap prior to its threading into the active site for cleavage. We also found that the β-pin region is rigidified into a short helix in R192F hFEN1-DNA structures, suppressing its gap endonuclease activity and cycle-dependent kinase interactions. Our findings suggest that a single mutation at the primary methylation site can alter the function of hFEN1 and provide insight into the role of the β-pin region in hFEN1 protein interactions that are essential for DNA replication and repair.

Articles - 5zod mentioned but not cited (1)

  1. Structural basis of 5' flap recognition and protein-protein interactions of human flap endonuclease 1. Xu H, Shi R, Han W, Cheng J, Xu X, Cheng K, Wang L, Tian B, Zheng L, Shen B, Hua Y, Zhao Y. Nucleic Acids Res 46 11315-11325 (2018)


Reviews citing this publication (3)

  1. Small-Molecule Inhibitors Targeting FEN1 for Cancer Therapy. Yang F, Hu Z, Guo Z. Biomolecules 12 1007 (2022)
  2. Implementing fluorescence enhancement, quenching, and FRET for investigating flap endonuclease 1 enzymatic reaction at the single-molecule level. Sobhy MA, Tehseen M, Takahashi M, Bralić A, De Biasio A, Hamdan SM. Comput Struct Biotechnol J 19 4456-4471 (2021)
  3. Okazaki fragment maturation: DNA flap dynamics for cell proliferation and survival. Sun H, Ma L, Tsai YF, Abeywardana T, Shen B, Zheng L. Trends Cell Biol 33 221-234 (2023)

Articles citing this publication (6)

  1. Mouse papillomavirus type 1 (MmuPV1) DNA is frequently integrated in benign tumors by microhomology-mediated end-joining. Yu L, Majerciak V, Xue XY, Uberoi A, Uberoi A, Lobanov A, Chen X, Cam M, Hughes SH, Lambert PF, Zheng ZM. PLoS Pathog 17 e1009812 (2021)
  2. Dynamic DNA-bound PCNA complexes co-ordinate Okazaki fragment synthesis, processing and ligation. Matsumoto Y, Brooks RC, Sverzhinsky A, Pascal JM, Tomkinson AE. J Mol Biol 432 166698 (2020)
  3. Biological and genomic characteristics of two bacteriophages isolated from sewage, using one multidrug-resistant and one non-multidrug-resistant strain of Klebsiella pneumoniae. Liang B, Zhao W, Han B, Barkema HW, Niu YD, Liu Y, Kastelic JP, Gao J. Front Microbiol 13 943279 (2022)
  4. miR-4324 inhibits ovarian cancer progression by targeting FEN1. Wu H, Yan Y, Yuan J, Luo M, Wang Y. J Ovarian Res 15 32 (2022)
  5. A high-specificity flap probe-based isothermal nucleic acid amplification method based on recombinant FEN1-Bst DNA polymerase. Ye X, Wang N, Li Y, Fang X, Kong J. Biosens Bioelectron 192 113503 (2021)
  6. Functional regulation of the structure-specific endonuclease FEN1 by the human cytomegalovirus protein IE1 suggests a role for the re-initiation of stalled viral replication forks. Schilling EM, Scherer M, Rothemund F, Stamminger T. PLoS Pathog 17 e1009460 (2021)


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