Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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BRCA1 Protein / drug effects
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BRCA1 Protein / genetics
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BRCA1 Protein / metabolism*
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Cell Death / physiology
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Cells, Cultured
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Cisplatin / pharmacology
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DNA Repair / physiology*
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DNA-Binding Proteins / drug effects
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Endodeoxyribonucleases / deficiency
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Endodeoxyribonucleases / genetics
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Endodeoxyribonucleases / metabolism*
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Flap Endonucleases
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Heterozygote
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Humans
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Huntington Disease / genetics
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Mice
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Mice, Knockout
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Mice, Transgenic
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Rad51 Recombinase
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Trinucleotide Repeat Expansion*
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Trinucleotide Repeats
Substances
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BRCA1 Protein
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DNA-Binding Proteins
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RAD51 protein, human
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Rad51 Recombinase
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Rad51 protein, mouse
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Endodeoxyribonucleases
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Flap Endonucleases
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FEN1 protein, human
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Cisplatin