Mammalian apurinic/apyrimidinic (
AP) endonuclease 1 (APE1), a ubiquitous and multifunctional
protein, plays an essential role in the repair of both endogenous and drug-induced
DNA damages in the genome. Unlike its E.coli counterpart Xth, mammalian APE1 has a unique N-terminal domain and possesses both DNA damage repair and transcriptional regulatory functions. Although the overexpression of APE1 in diverse
cancer types and the association of APE1 expression with
chemotherapy resistance and poor prognosis are well documented, the cellular and molecular mechanisms that alter APE1 functions during
tumorigenesis are largely unknown. Here, we show the presence of full-length APE1 and N-terminal truncated
isoforms of APE1 in
tumor tissue samples of various
cancer types. However, primary
tumor tissue has higher levels of acetylated APE1 (AcAPE1) as well as full-length APE1 compared to adjacent non-
tumor tissue. We found that APE1 is proteolytically cleaved by an unknown
serine protease at its N-terminus following residue
lysine (Lys) Lys6 and/or Lys7 and after Lys27 and Lys31 or Lys32. Acetylation of these Lys residues in APE1 prevents this proteolysis. The N-terminal domain of APE1 and its acetylation are required for modulation of the expression of hundreds of genes. Importantly, we found that AcAPE1 is essential for sustained cell proliferation. Together, our study demonstrates that increased acetylation levels of APE1 in
tumor cells inhibit the limited N-terminal proteolysis of APE1 and thereby maintain the functions of APE1 to promote
tumor cells' sustained proliferation and survival.