AP endonuclease 1 prevents trinucleotide repeat expansion via a novel mechanism during base excision repair

Nucleic Acids Res. 2015 Jul 13;43(12):5948-60. doi: 10.1093/nar/gkv530. Epub 2015 May 18.

Abstract

Base excision repair (BER) of an oxidized base within a trinucleotide repeat (TNR) tract can lead to TNR expansions that are associated with over 40 human neurodegenerative diseases. This occurs as a result of DNA secondary structures such as hairpins formed during repair. We have previously shown that BER in a TNR hairpin loop can lead to removal of the hairpin, attenuating or preventing TNR expansions. Here, we further provide the first evidence that AP endonuclease 1 (APE1) prevented TNR expansions via its 3'-5' exonuclease activity and stimulatory effect on DNA ligation during BER in a hairpin loop. Coordinating with flap endonuclease 1, the APE1 3'-5' exonuclease activity cleaves the annealed upstream 3'-flap of a double-flap intermediate resulting from 5'-incision of an abasic site in the hairpin loop. Furthermore, APE1 stimulated DNA ligase I to resolve a long double-flap intermediate, thereby promoting hairpin removal and preventing TNR expansions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA / chemistry
  • DNA / metabolism
  • DNA Ligase ATP
  • DNA Ligases / metabolism
  • DNA Repair*
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / metabolism*
  • Exodeoxyribonucleases / metabolism
  • Flap Endonucleases / metabolism
  • Nucleic Acid Conformation
  • Trinucleotide Repeat Expansion*

Substances

  • LIG1 protein, human
  • DNA
  • Exodeoxyribonucleases
  • Flap Endonucleases
  • DNA-(Apurinic or Apyrimidinic Site) Lyase
  • DNA Ligases
  • DNA Ligase ATP