Title: AP endonuclease 1 prevents trinucleotide repeat expansion via a novel mechanism during base excision repair.
Authors: Beaver, Jill M; Lai, Yanhao; Xu, Meng; Casin, Astrid H; Laverde, Eduardo E; Liu, Yuan
Published In Nucleic Acids Res, (2015 Jul 13)
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.
PubMed ID: 25990721
MeSH Terms: DNA Ligase ATP; DNA Ligases/metabolism; DNA Repair*; DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism*; DNA/chemistry; DNA/metabolism; Exodeoxyribonucleases/metabolism; Flap Endonucleases/metabolism; Nucleic Acid Conformation; Trinucleotide Repeat Expansion*