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J. Biol. Chem., Vol. 275, Issue 22, 16420-16427, June 2, 2000
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From the Department of Biochemistry and Biophysics and the Cancer
Center, University of Rochester School of Medicine and Dentistry,
Rochester, New York 14642
Recent genetic evidence indicates that null
mutants of the 5'-flap endonuclease (FEN1) result in an expansion of
repetitive sequences. The substrate for FEN1 is a flap formed by
natural 5'-end displacement of the short intermediates of lagging
strand replication. FEN1 binds the 5'-end of the flap, tracks to the point of annealing at the base of the flap, and then cleaves. Here we
examine mechanisms by which foldback structures within the flap could
contribute to repeat expansions. Cleavage by FEN1 was reduced with
increased length of the foldback. However, even the longest foldbacks
were cleaved at a low rate. Substrates containing the repetitive
sequence CTG also were cleaved at a reduced rate. Bubble substrates,
likely intermediates in repeat expansions, were inhibitory. Neither
replication protein A nor proliferating cell nuclear antigen were able
to assist in the removal of secondary structure within a flap. We
propose that FEN1 cleaves natural foldbacks at a reduced rate. However,
although the cleavage delay is not likely to influence the overall
process of chromosomal replication, specific foldbacks could inhibit
cleavage sufficiently to result in duplication of the foldback sequence.
Inhibition of Flap Endonuclease 1 by Flap Secondary Structure and
Relevance to Repeat Sequence Expansion*
*
This work was supported by National Institutes of Health
Grant GM24441 and Fellowship Grant GM18961 (to L. A. H.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The 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: University of
Rochester Medical Center, Dept. of Biochemistry & Biophysics, 601 Elmwood Ave., Box 712, Rochester, NY 14642. Tel.: 716-275-3269; Fax:
716-271-2683; E-mail: robert_bambara@urmc.rochester.edu.
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