AP endonuclease 1 prevents trinucleotide repeat expansion via a novel mechanism during base excision repair. Issue 12 (18th May 2015)

• Record Type: Journal Article
• Authors: Beaver, Jill M.; Lai, Yanhao; Xu, Meng; Casin, Astrid H.; Laverde, Eduardo E.; Liu, Yuan
• Is Part Of: Nucleic acids research. Volume 43:Issue 12(2015)
• Page Start: 5948
• Page End: 5960
• Publication Date: 2015-05-18
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkv530
• Languages: English
• ISSNs: 0305-1048

Abstract

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.