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Nucleic Acids Research 2005 33(21):6769-6781; doi:10.1093/nar/gki1002
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Published online 2 December 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
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Article

The interaction site of Flap Endonuclease-1 with WRN helicase suggests a coordination of WRN and PCNA

Sudha Sharma, Joshua A. Sommers, Ronald K. Gary1, Erica Friedrich-Heineken2, Ulrich Hübscher2 and Robert M. Brosh, Jr*

Laboratory of Molecular Gerontology, National Institute on Aging, NIH 5600 Nathan Shock Drive, Baltimore, MD 21224, USA 1Department of Chemistry, University of Nevada Las Vegas 4505 Maryland Parkway, Las Vegas, NV 89154-4003, USA 2Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich-Irchel Winterthurerstrasse 190, CH-8057 Zürich, Switzerland

*To whom correspondence should be addressed. Tel: +1 410 558 8578; Fax: +1 410 558 8157; Email: BroshR{at}grc.nia.nih.gov

Received October 7, 2005. Revised November 17, 2005. Accepted November 17, 2005.

Werner and Bloom syndromes are genetic RecQ helicase disorders characterized by genomic instability. Biochemical and genetic data indicate that an important protein interaction of WRN and Bloom syndrome (BLM) helicases is with the structure-specific nuclease Flap Endonuclease 1 (FEN-1), an enzyme that is implicated in the processing of DNA intermediates that arise during cellular DNA replication, repair and recombination. To acquire a better understanding of the interaction of WRN and BLM with FEN-1, we have mapped the FEN-1 binding site on the two RecQ helicases. Both WRN and BLM bind to the extreme C-terminal 18 amino acid tail of FEN-1 that is adjacent to the PCNA binding site of FEN-1. The importance of the WRN/BLM physical interaction with the FEN-1 C-terminal tail was confirmed by functional interaction studies with catalytically active purified recombinant FEN-1 deletion mutant proteins that lack either the WRN/BLM binding site or the PCNA interaction site. The distinct binding sites of WRN and PCNA and their combined effect on FEN-1 nuclease activity suggest that they may coordinately act with FEN-1. WRN was shown to facilitate FEN-1 binding to its preferred double-flap substrate through its protein interaction with the FEN-1 C-terminal binding site. WRN retained its ability to physically bind and stimulate acetylated FEN-1 cleavage activity to the same extent as unacetylated FEN-1. These studies provide new insights to the interaction of WRN and BLM helicases with FEN-1, and how these interactions might be regulated with the PCNA–FEN-1 interaction during DNA replication and repair.


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