title: Inhibition of FEN-1 processing by DNA secondary structure at trinucleotide repeats.
abstract: 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.
authors.affiliation: Department of Pharmacology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
authors.forename: C
authors.initials: C
authors.lastname: Spiro
authors.forename: R
authors.initials: R
authors.lastname: Pelletier
authors.forename: M L
authors.initials: ML
authors.lastname: Rolfsmeier
authors.forename: M J
authors.initials: MJ
authors.lastname: Dixon
authors.forename: R S
authors.initials: RS
authors.lastname: Lahue
authors.forename: G
authors.initials: G
authors.lastname: Gupta
authors.forename: M S
authors.initials: MS
authors.lastname: Park
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: S V
authors.initials: SV
authors.lastname: Mariappan
authors.forename: C T
authors.initials: CT
authors.lastname: McMurray
mesh_terms: D004247:DNA / Q000737:chemistry / Q000235:genetics*; D004706:Endodeoxyribonucleases / Q000235:genetics*; D045585:Flap Endonucleases; D005786:Gene Expression Regulation; D006801:Humans; D009690:Nucleic Acid Conformation; D018911:Trinucleotide Repeats / Q000235:genetics*
chemical_list: D004247:DNA; D004706:Endodeoxyribonucleases; D045585:Flap Endonucleases; C468317:FEN1 protein, human