title: Novel function of the flap endonuclease 1 complex in processing stalled DNA replication forks.
abstract: Restarting stalled replication forks partly depends on the break-induced recombination pathway, in which a DNA double-stranded break (DSB) is created on the stalled replication fork to initiate the downstream recombination cascades. Single-stranded DNA gaps accumulating on stalled replication forks are potential targets for endonucleases to generate DSBs. However, it is unclear how this process is executed and which nucleases are involved in eukaryotic cells. Here, we identify a novel gap endonuclease (GEN) activity of human flap endonuclease 1 (FEN-1), critical in resolving stalled replication fork. In response to replication arrest, FEN-1 interacts specifically with Werner syndrome protein for efficient fork cleavage. Replication protein A facilitates FEN-1 interaction with DNA bubble structures. Human FEN-1, but not the GEN-deficient mutant, E178A, was shown to rescue the defect in resistance to UV and camptothecin in a yeast FEN-1 null mutant.
authors.affiliation: Department of Radiation Biology, City of Hope National Medical Center and Beckman Research Institute, Duarte, California 91010, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zheng
authors.forename: Mian
authors.initials: M
authors.lastname: Zhou
authors.forename: Qing
authors.initials: Q
authors.lastname: Chai
authors.forename: Jay
authors.initials: J
authors.lastname: Parrish
authors.forename: Ding
authors.initials: D
authors.lastname: Xue
authors.forename: Steve M
authors.initials: SM
authors.lastname: Patrick
authors.forename: John J
authors.initials: JJ
authors.lastname: Turchi
authors.forename: Steven M
authors.initials: SM
authors.lastname: Yannone
authors.forename: David
authors.initials: D
authors.lastname: Chen
authors.forename: Binghui
authors.initials: B
authors.lastname: Shen
mesh_terms: D002457:Cell Extracts; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D004261:DNA Replication; D045585:Flap Endonucleases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D009154:Mutation / Q000235:genetics; D014898:Werner Syndrome / Q000378:metabolism
chemical_list: D002457:Cell Extracts; D004247:DNA; D045585:Flap Endonucleases; C468317:FEN1 protein, human