Secrets of a precision protein machine unlocked by experts

The basic details of the mechanism of FEN-1, a key player in DNA replication and repair, have been deciphered by a team of experts, including an academic group from the University of Sheffield.

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, the DNA-slicing "flap endonuclease" FEN-1 plays an essential role.

The way FEN-1 works, one of the most important of a superfamily of similar proteins, has now been determined by an international team of scientists led by John Tainer from the United States Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab), the Scripps Research Institute in La Jolla (Scripps) and Dr Jane Grasby from the University of Sheffield. Their combined structure and functional studies, the results of which were published in the 15 April 2011sue of Cell, reveal the surprising mechanism behind FEN-1's speed, accuracy, and versatility.

FEN-1 has to quickly perform 50 million operations during each replication but 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.

The team wanted to know how FEN-1 can perform different functions and how the larger family of which it is a member can perform similar functions on very dissimilar arrangements of DNA. The secret of how FEN-1 interacts with DNA lies in its structure.

All replication starts by unzipping double-strand DNA; the resulting single strands are then reconstructed as duplicates of the original double strand by adding complementary nucleotides.