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Nucleic Acids Research 2006 34(6):1772-1784; doi:10.1093/nar/gkl106
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Published online 31 March 2006

© The Author 2006. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Article

The DNA–protein interaction modes of FEN-1 with gap substrates and their implication in preventing duplication mutations

Ren Liu1,2, Junzhuan Qiu1, L. David Finger1, Li Zheng1 and Binghui Shen1,2,*

1 Department of Radiation Biology, City of Hope National Medical Center and Beckman Research Institute Duarte, CA 91010, USA 2 Graduate Program in Biological Sciences, City of Hope National Medical Center and Beckman Research Institute Duarte, CA 91010, USA

*To whom correspondence should be addressed. Tel: +1 626 301 8879; Fax: +1 626 301 8280; Email: bshen{at}coh.org

Received January 23, 2006. Revised February 14, 2006. Accepted March 8, 2006.

Flap endonuclease-1 (FEN-1) is a structure-specific nuclease best known for its involvement in RNA primer removal and long-patch base excision repair. This enzyme is known to possess 5'-flap endo- (FEN) and 5'–3' exo- (EXO) nuclease activities. Recently, FEN-1 has been reported to also possess a gap endonuclease (GEN) activity, which is possibly involved in apoptotic DNA fragmentation and the resolution of stalled DNA replication forks. In the current study, we compare the kinetics of these activities to shed light on the aspects of DNA structure and FEN-1 DNA-binding elements that affect substrate cleavage. By using DNA binding deficient mutants of FEN-1, we determine that the GEN activity is analogous to FEN activity in that the single-stranded DNA region of DNA substrates interacts with the clamp region of FEN-1. In addition, we show that the C-terminal extension of human FEN-1 likely interacts with the downstream duplex portion of all substrates. Taken together, a substrate-binding model that explains how FEN-1, which has a single active center, can have seemingly different activities is proposed. Furthermore, based on the evidence that GEN activity in complex with WRN protein cleaves hairpin and internal loop substrates, we suggest that the GEN activity may prevent repeat expansions and duplication mutations.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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