title: Human Apurinic/Apyrimidinic Endonuclease (APE1) Is Acetylated at DNA Damage Sites in Chromatin, and Acetylation Modulates Its DNA Repair Activity.
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 sitesin vitrohas 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, unlikeSaccharomyces cerevisiaeorEscherichia colicells, 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.
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Shrabasti
authors.initials: S
authors.lastname: Roychoudhury
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Somsubhra
authors.initials: S
authors.lastname: Nath
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Heyu
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Muralidhar L
authors.initials: ML
authors.lastname: Hegde
authors.affiliation: Nikon Instrument Inc., Memphis, Tennessee, USA.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Bellot
authors.affiliation: Central University of Punjab, Bathinda, India.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Mantha
authors.affiliation: Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Shiladitya
authors.initials: S
authors.lastname: Sengupta
authors.affiliation: Department of Pediatrics, Hematology/Oncology Division, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Sutapa
authors.initials: S
authors.lastname: Ray
authors.affiliation: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska, USA.|Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Amarnath
authors.initials: A
authors.lastname: Natarajan
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, USA kishor.bhakat@unmc.edu.|Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Kishor K
authors.initials: KK
authors.lastname: Bhakat
mesh_terms: D000107:Acetylation; D055162:Biocatalysis; D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D002843:Chromatin / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000737:chemistry / Q000378:metabolism*; D016678:Genome; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008954:Models, Biological; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D002843:Chromatin; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D008239:Lysine
keywords: AP site; APE1; DNA damage; acetylation; base excision repair; endogenous DNA damage