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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.

SUBMITTER: Beaver JM 

PROVIDER: S-EPMC4499148 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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

Beaver Jill M JM   Lai Yanhao Y   Xu Meng M   Casin Astrid H AH   Laverde Eduardo E EE   Liu Yuan Y  

Nucleic acids research 20150518 12

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 expa  ...[more]

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