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Werner syndrome (WS) is a human premature aging disorder characterized by chromosomal instability. The cellular defects of WS presumably reflect compromised or aberrant function of a DNA metabolic pathway that under normal circumstances confers stability to the genome. We report a novel interaction of the WRN gene product with the human 5' flap endonuclease/5'-3' exonuclease (FEN-1), a DNA structure-specific nuclease implicated in DNA replication, recombination and repair. WS protein (WRN) dramatically stimulates the rate of FEN-1 cleavage of a 5' flap DNA substrate. The WRN-FEN-1 functional interaction is independent of WRN catalytic function and mediated by a 144 amino acid domain of WRN that shares homology with RecQ DNA helicases. A physical interaction between WRN and FEN-1 is demonstrated by their co-immunoprecipitation from HeLa cell lysate and affinity pull-down experiments using a recombinant C-terminal fragment of WRN. The underlying defect of WS is discussed in light of the evidence for the interaction between WRN and FEN-1.

Original publication

DOI

10.1093/emboj/20.20.5791

Type

Journal article

Journal

EMBO J

Publication Date

15/10/2001

Volume

20

Pages

5791 - 5801

Keywords

Adenosine Triphosphatases, Catalysis, DNA, DNA Helicases, DNA-Binding Proteins, Endodeoxyribonucleases, Enzyme Activation, Exodeoxyribonucleases, Exonucleases, Flap Endonucleases, HeLa Cells, Humans, Macromolecular Substances, Peptide Fragments, Proliferating Cell Nuclear Antigen, Protein Structure, Tertiary, RecQ Helicases, Recombinant Fusion Proteins, Replication Protein A, Werner Syndrome, Werner Syndrome Helicase