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.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Spiro C,McMurray CTdoi
10.1128/mcb.23.17.6063-6074.2003subject
Has Abstractpub_date
2003-09-01 00:00:00pages
6063-74issue
17eissn
0270-7306issn
1098-5549journal_volume
23pub_type
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