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Nuclease-deficient FEN-1 blocks Rad51/BRCA1-mediated repair and causes trinucleotide repeat instability

Craig Spiro1, Cynthia T McMurray

  • 1Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.

Molecular and Cellular Biology
|August 15, 2003
PubMed

Insights

Faulty human flap endonuclease (FEN1) processing causes repeat instability in cells and Huntington

Area of Science:

  • Molecular Biology
  • Genetics
  • DNA Repair

Background:

  • Expansion-prone repeats form structures that inhibit human flap endonuclease (FEN1).
  • Repeat instability is a hallmark of several genetic disorders.

Purpose of the Study:

  • To investigate the role of FEN1 in repeat instability.
  • To determine if faulty FEN1 processing initiates repeat instability in mammalian cells.

Main Methods:

  • Analyzing Huntington's disease mice with varying FEN1 genotypes.
  • Expressing nuclease-defective FEN1 in human cells.
  • Assessing DNA repair pathways and complex formation.

Main Results:

  • FEN1 deficiency leads to repeat expansions in Huntington's disease mice.
  • Nuclease-defective FEN1 causes repeat instability and aberrant DNA repair in human cells.
  • Inefficient flap processing by FEN1 disrupts Rad51/BRCA1 complex formation.

Conclusions:

  • Faulty FEN1 processing is a key initiator of repeat instability.
  • FEN1 dysfunction impacts DNA repair pathways, contributing to genetic instability.

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