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Molecular and Cellular Biology, September 2003, p. 6063-6074, Vol. 23, No. 17
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.17.6063-6074.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Nuclease-Deficient FEN-1 Blocks Rad51/BRCA1-Mediated Repair and Causes Trinucleotide Repeat Instability

Department of Molecular Pharmacology and Experimental Therapeutics,¹ Department of Biochemistry and Molecular Biology and Molecular Neuroscience Program, Mayo Clinic and Foundation, Rochester, Minnesota 55905²

Received 13 March 2003/ Returned for modification 22 April 2003/ Accepted 8 May 2003

Previous studies have shown that expansion-prone repeats form structures that inhibit human flap endonuclease (FEN-1). We report here that faulty processing by FEN-1 initiates repeat instability in mammalian cells. Disease-length CAG tracts in Huntington's disease mice heterozygous for FEN-1 display a tendency toward expansions over contractions during intergenerational inheritance compared to those in homozygous wild-type mice. Further, with regard to human cells expressing a nuclease-defective FEN-1, we provide direct evidence that an unprocessed FEN-1 substrate is a precursor to instability. In cells with no endogenous defects in DNA repair, exogenous nuclease-defective FEN-1 causes repeat instability and aberrant DNA repair. Inefficient flap processing blocks the formation of Rad51/BRCA1 complexes but invokes repair by other pathways.

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