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J. Biol. Chem., Vol. 280, Issue 7, 5391-5399, February 18, 2005

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Human Bloom Protein Stimulates Flap Endonuclease 1 Activity by Resolving DNA Secondary Structure^*

Wensheng Wang and Robert A. Bambara

From the Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Flap endonuclease 1 (FEN1) participates in removal of RNA primers of Okazaki fragments, several DNA repair pathways, and genome stability maintenance. Defects in yeast FEN1 produce chromosomal instability, hyper-recombination, and sequence duplication. These occur because flaps produced during replication are not promptly removed. Long-lived flaps sustain breaks and form misaligned bubble structures that produce duplications. Flaps that can form secondary structure inhibit even wild-type FEN1 and are more likely to form bubbles. Although proliferating cell nuclear antigen stimulates FEN1, it cannot resolve secondary structures. Bloom protein (BLM) is a 3'-5' helicase, mutated in Bloom syndrome. BLM has been reported to interact with and stimulate FEN1 independent of helicase function. We found activation of the helicase by ATP did not alter BLM stimulation of cleavage of unstructured flaps. However, BLM stimulation of FEN1 cleavage of foldback flaps, bubbles, or triplet repeats was increased by an additional increment when ATP was added. Helicase-dependent stimulation of FEN1 cleavage was robust over a range of sizes of the single-stranded part of bubbles. However, increasing the length of the 5' annealed region of the bubble ultimately counteracted the stimulatory capacity of the BLM helicase. Moderate helicase-dependent stimulation was observed with both fixed and equilibrating CTG flaps. Our results suggest that BLM suppresses genome instability by aiding FEN1 cleavage of structure-containing flaps.

Received for publication, November 1, 2004 , and in revised form, November 30, 2004.

^* This work was supported by National Institutes of Health Grant GM024441 (to R. A. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Biochemistry and Biophysics, Box 712, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Rochester, NY 14642. E-mail: robert_bambara{at}urmc.rochester.edu.

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