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Published online 6 May 2004

Nucleic Acids Research, 2004, Vol. 32, No. 8 2520-2528
© 2004 Oxford University Press

The Fen1 extrahelical 3'-flap pocket is conserved from archaea to human and regulates DNA substrate specificity

Erica Friedrich-Heineken and Ulrich Hübscher*

Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich, Winterthurerstrasse 190, CH 8057 Zürich, Switzerland

*To whom correspondence should be addressed. Tel: +41 1 6355472; Fax: +41 1 6356840; Email: hubscher{at}vetbio.unizh.ch

Received February 20, 2004; Revised March 24, 2004; Accepted April 12, 2004

Fen1 is a key enzyme for the maintenance of genetic stability in archaea and eukaryotes and is classified as a tumor suppressor. Very recent structural data obtained from Archaeoglobus fulgidus Fen1 suggest that an extrahelical 3'-flap pocket is responsible for substrate specificity, by binding to the unpaired 3'-flap and by opening and kinking the DNA. Since the extrahelical 3'-flap pocket in archaeal Fen1 contains seven amino acids that are conserved to a great extent in human Fen1, we have mutated the four conserved or all seven amino acids in the human Fen1 extrahelical 3'-flap pocket to alanine. Our data suggest that the human extrahelical 3'-flap pocket mutants have lost substrate specificity to the double-flap DNA. Moreover, loss of high affinity for the unpaired 3'-flap suggests that the extrahelical 3'-flap pocket is essential for recognition and processing of the ‘physiological’ template. Human PCNA could stimulate the human Fen1 extrahelical 3'-flap pocket mutants but not restore their specificity. Thus the substrate specificity of Fen1 has been functionally conserved over a billion years from archaea to human.


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