Abstract
ABSTRACTApurinic/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.
Highlights
Apurinic/apyrimidinic (AP) sites, the most frequently formed DNA lesions in the genome, inhibit transcription and block replication
Using conditional APE1-nullizygous mouse embryo fibroblasts (MEF), we showed that acetylable lysine 6 (Lys6) and Lys7 residues of APE1 are essential for cell survival [13]
We show that APE1 is acetylated after binding to the AP sites in the chromatin and that AcAPE1 is exclusively associated with chromatin throughout the cell cycle
Summary
Apurinic/apyrimidinic (AP) sites, the most frequently formed DNA lesions in the genome, inhibit transcription and block replication. AP sites can be generated either spontaneously through water-mediated depurination or depyrimidination or after removal of oxidized and modified bases by DNA glycosylases [2] Thousands of such AP sites are generated daily in the genome of a human cell [1]. Human APE1 is a ubiquitous and multifunctional protein [5] It was originally discovered as a DNA repair enzyme playing a central role in the repair of spontaneously generated AP sites and oxidative and alkylated DNA damage in the genome via the BER pathway [6,7,8]. Our study shows that acetylation of APE1 plays a crucial role in the repair of AP sites and oxidative and alkylated base damage in the genome and promotes cell survival and proliferation
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