Abstract
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.
Highlights
Apurinic/apyrimidinic (AP) endonuclease 1 (APE1) is the primary enzyme in mammals responsible for the repair of spontaneously generated abasic sites in the genome [1, 2]
The predominant APE1 band observed in all nontumor tissue had faster mobility compared to the 37 kD band corresponding to APE1 present in cultured lung adenocarcinoma A549 cells and full-length (FL) recombinant (Rec.) APE1 (Figures 1A&1C)
To further confirm that the N-terminal domain of APE1 and its acetylation are involved in modulating gene expression, we examined the effect of ectopic WT, non-acetylable K6R/K7R (RR) or N-terminal 42 aa deleted (N∆42) APE1 mutants
Summary
Apurinic/apyrimidinic (AP) endonuclease 1 (APE1) is the primary enzyme in mammals responsible for the repair of spontaneously generated abasic sites in the genome [1, 2]. Human APE1 has an N-terminal disordered domain (1-42 amino acid; aa) and possesses both DNA repair and transcriptional regulatory activities [16]. We reported that Lys and Lys in the N-terminal domain of APE1 can be acetylated (AcAPE1) by the histone acetyltransferase (HAT) p300 in cultured cells and this acetylation modulates the transcriptional co-regulatory activity of APE1 [9, 11, 18]. Other Lys residues (Lys and 35) in the N-terminal domain of APE1 are found to be modified by acetylation in HeLa cells and mutation of these residues can modulate the DNA damage repair activity of APE1 [19]
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