Inhibition of FEN-1 processing by DNA secondary structure at trinucleotide repeats

Mol Cell. 1999 Dec;4(6):1079-85. doi: 10.1016/s1097-2765(00)80236-1.


The mechanism by which trinucleotide expansion occurs in human genes is not understood. However, it has been hypothesized that DNA secondary structure may actively participate by preventing FEN-1 cleavage of displaced Okazaki fragments. We show here that secondary structure can, indeed, play a role in expansion by a FEN-1-dependent mechanism. Secondary structure inhibits flap processing at CAG, CGG, or CTG repeats in a length-dependent manner by concealing the 5' end of the flap that is necessary for both binding and cleavage by FEN-1. Thus, secondary structure can defeat the protective function of FEN-1, leading to site-specific expansions. However, when FEN-1 is absent from the cell, alternative pathways to simple inhibition of flap processing contribute to expansion.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • DNA / chemistry
  • DNA / genetics*
  • Endodeoxyribonucleases / genetics*
  • Flap Endonucleases
  • Gene Expression Regulation
  • Humans
  • Nucleic Acid Conformation*
  • Trinucleotide Repeats / genetics*


  • DNA
  • Endodeoxyribonucleases
  • Flap Endonucleases
  • FEN1 protein, human