title: Regulation of limited N-terminal proteolysis of APE1 in tumor via acetylation and its role in cell proliferation.
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.
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE-68198, USA.|Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE-68198, USA.|Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX-77555, USA.
authors.forename: Kishor K
authors.initials: KK
authors.lastname: Bhakat
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX-77555, USA.|Current Affiliation: Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX-77030, USA.
authors.forename: Shiladitya
authors.initials: S
authors.lastname: Sengupta
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX-77555, USA.
authors.forename: Victor F
authors.initials: VF
authors.lastname: Adeniyi
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE-68198, 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, NE-68198, USA.|Current Affiliation: Molecular Biology Research and Diagnostic Laboratory, Saroj Gupta Cancer Centre and Research Institute (SGCC & RI), Kolkata-63, India.
authors.forename: Somsubhra
authors.initials: S
authors.lastname: Nath
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX-77555, USA.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Bellot
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE-68198, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Feng
authors.affiliation: Center for Animal Sciences, School of Basic and Applied Sciences, Central University of Punjab, Bathinda, Punjab 151001, India.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Mantha
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX-77555, USA.|Bioinformatics Program, University of Texas Medical Branch, Galveston, TX-77555, USA.
authors.forename: Mala
authors.initials: M
authors.lastname: Sinha
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, TX-77555, USA.
authors.forename: Suimin
authors.initials: S
authors.lastname: Qiu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX-77555, USA.|Bioinformatics Program, University of Texas Medical Branch, Galveston, TX-77555, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Luxon
mesh_terms: D000107:Acetylation; D049109:Cell Proliferation / Q000502:physiology*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D059748:Proteolysis; D014407:Tumor Cells, Cultured
chemical_list: C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: APE1; acetylation; base excision repair; proliferation; proteolysis