title: AP endonuclease 1 prevents trinucleotide repeat expansion via a novel mechanism during base excision repair.
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.
authors.affiliation: Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA Biochemistry Ph.D. Program, Florida International University, Miami, FL 33199, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Beaver
authors.affiliation: Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA.
authors.forename: Yanhao
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA.
authors.forename: Astrid H
authors.initials: AH
authors.lastname: Casin
authors.affiliation: Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA.
authors.forename: Eduardo E
authors.initials: EE
authors.lastname: Laverde
authors.affiliation: Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA Biochemistry Ph.D. Program, Florida International University, Miami, FL 33199, USA Biomolecular Sciences Institute, School of Integrated Sciences and Humanities, Florida International University, Miami, FL 33199, USA yualiu@fiu.edu.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
mesh_terms: D004247:DNA / Q000737:chemistry / Q000378:metabolism; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000378:metabolism; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D005090:Exodeoxyribonucleases / Q000378:metabolism; D045585:Flap Endonucleases / Q000378:metabolism; D009690:Nucleic Acid Conformation; D019680:Trinucleotide Repeat Expansion
chemical_list: C000607892:LIG1 protein, human; D004247:DNA; D005090:Exodeoxyribonucleases; D045585:Flap Endonucleases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D011088:DNA Ligases; D000072481:DNA Ligase ATP