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Papers In Press, published online ahead of print March 22, 2004
Department of Radiation Research, City of Hope National Medical Center, Duarte, CA 91010
Corresponding Author: bshen{at}coh.org
Flap endonuclease-1 or FEN-1 is a structure-specific and multifunctional nuclease critical for DNA replication, repair and recombination; however, its interaction with DNA substrates has not been fully understood. In the current study, we have defined the borders of the interaction between the FEN-1 protein and its DNA substrates and identified six clusters of conserved positively charged amino acid residues, which are in direct contact with DNA substrate. To further map the corresponding interactions between FEN-1 residues and DNA substrates, we performed biochemical assays employing a series of flap DNA substrates lacking some structural components and a series of binding deficient point mutants of FEN-1. It was revealed that R47, R70, and K326/R327 of FEN-1 interact with the upstream duplex of DNA substrates, whereas K244/R245 interacts with the downstream duplex. This result indicates the orientation of the DNA/FEN-1 protein interaction. Moreover, R70 and R47 were determined to interact with the sites around the second nucleotide (R70) or the fifth/sixth nucleotide (R47) of the template strand in the upstream duplex portion counting from the nick point of the flap substrate. Together with previously published data and the crystallographic information from the FEN-1/DNA complex that we published recently (Chapados et al., 2004, Cell, 116, 39059), we are able to propose a reasonable model for how the human FEN-1 protein interacts with its DNA substrates.
J. Biol. Chem, 10.1074/jbc.M401464200
Submitted on February 10, 2004
Revised on March 17, 2004
Accepted on March 22, 2004
Interaction Interface of human flap endonuclease-1 with Its DNA substrates
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