DNA replication is critical to the life of all organisms, insuring that each new cell, as well as each new offspring, gets an accurate copy of the genome. Among the legions of proteins that do the work so essential to a cell's survival, the DNA-slicing "flap endonuclease" FEN1 plays a key role.
The structure of human FEN1 has now been solved by an international team of scientists led by the U.S. Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab) and the Scripps Research Institute in La Jolla (Scripps). The structure reveals the surprising mechanism behind FEN1's speed, accuracy, and versatility.
"FEN1 has to perform 50 million operations during each replication. It has to do them quickly and it can't be sloppy," says John Tainer of Berkeley Lab's Life Sciences Division (LSD) and Scripps. "But FEN1 is also important in DNA repair, which presents different challenges. Its ability to target specific repair pathways makes it of urgent interest in cancer research."
"We wanted to know how FEN1 can do different jobs, and how the larger family of which it's a member can perform similar functions on very dissimilar arrangements of DNA," says Susan Tsutakawa of LSD, first author of a paper in the journal Cell describing the team's work. "The secret of how FEN1 interacts with DNA lies in its structure."
In the beginning, replication
When a cell reproduces itself, the critical first step is DNA replication, which starts by unwinding double-stranded DNA. The resulting single-strand "templates" are then processed by intricate cellular machinery to form two duplicates of the original double helix.
Much of the work is done by a protein called DNA polymerase, which adds nucleotides complementary to the template's nucleotides. But polymerase can't build the copy without help; first an RNA primer has to bind to the template with a few base pairs, acting as a short length of
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DOE/Lawrence Berkeley National Laboratory