AP endonuclease 1 prevents trinucleotide repeat expansion via a novel mechanism during base excision repair |
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| Authors: | Jill M Beaver Yanhao Lai Meng Xu Astrid H Casin Eduardo E Laverde Yuan Liu |
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| Institution: | 1Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA;2Biochemistry Ph.D. Program, Florida International University, Miami, FL 33199, USA;3Biomolecular Sciences Institute, School of Integrated Sciences and Humanities, Florida International University, Miami, FL 33199, USA |
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| 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. |
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