First Author | Spiro C | Year | 2003 |
Journal | Mol Cell Biol | Volume | 23 |
Issue | 17 | Pages | 6063-74 |
PubMed ID | 12917330 | Mgi Jnum | J:85041 |
Mgi Id | MGI:2671555 | Doi | 10.1128/MCB.23.17.6063-6074.2003 |
Citation | Spiro C, et al. (2003) Nuclease-deficient FEN-1 blocks Rad51/BRCA1-mediated repair and causes trinucleotide repeat instability. Mol Cell Biol 23(17):6063-74 |
abstractText | 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. |