Human apurinic/apyrimidinic endonuclease (APE1) is acetylated at DNA damage sites in chromatin, and acetylation modulates its DNA repair activity

Shrabasti Roychoudhury, Somsubhra Nath, Heyu Song, Muralidhar L. Hegde, Larry J. Bellot, Anil K. Mantha, Shiladitya Sengupta, Sutapa Ray, Amarnath Natarajan, Kishor K. Bhakat

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Apurinic/apyrimidinic (AP) sites, the most frequently formed DNA lesions in the genome, inhibit transcription and block replication. The primary enzyme that repairs AP sites in mammalian cells is the AP endonuclease (APE1), which functions through the base excision repair (BER) pathway. Although the mechanism by which APE1 repairs AP sites in vitro has been extensively investigated, it is largely unknown how APE1 repairs AP sites in cells. Here, we show that APE1 is acetylated (AcAPE1) after binding to the AP sites in chromatin and that AcAPE1 is exclusively present on chromatin throughout the cell cycle. Positive charges of acetylable lysine residues in the N-terminal domain of APE1 are essential for chromatin association. Acetylation-mediated neutralization of the positive charges of the lysine residues in the N-terminal domain of APE1 induces a conformational change; this in turn enhances the AP endonuclease activity of APE1. In the absence of APE1 acetylation, cells accumulated AP sites in the genome and showed higher sensitivity to DNA-damaging agents. Thus, mammalian cells, unlike Saccharomyces cerevisiae or Escherichia coli cells, require acetylation of APE1 for the efficient repair of AP sites and base damage in the genome. Our study reveals that APE1 acetylation is an integral part of the BER pathway for maintaining genomic integrity.

Original languageEnglish (US)
Article numbere00401-16
JournalMolecular and cellular biology
Volume37
Issue number6
DOIs
StatePublished - 2017

Keywords

  • AP site
  • APE1
  • Acetylation
  • Base excision repair
  • DNA damage
  • Endogenous DNA damage

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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