期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 23, 期 17, 页码 6063-6074出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.23.17.6063-6074.2003
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资金
- NIDDK NIH HHS [DK 43694] Funding Source: Medline
- NIMH NIH HHS [MH5608] Funding Source: Medline
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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