title: Elevated level of acetylation of APE1 in tumor cells modulates DNA damage repair.
abstract: Apurinic/apyrimidinic (AP) sites are frequently generated in the genome by spontaneous depurination/depyrimidination or after removal of oxidized/modified bases by DNA glycosylases during the base excision repair (BER) pathway. Unrepaired AP sites are mutagenic and block DNA replication and transcription. The primary enzyme to repair AP sites in mammalian cells is AP endonuclease (APE1), which plays a key role in this repair pathway. Although overexpression of APE1 in diverse cancer types and its association with chemotherapeutic resistance are well documented, alteration of posttranslational modification of APE1 and modulation of its functions during tumorigenesis are largely unknown. Here, we show that both classical histone deacetylase HDAC1 and NAD+-dependent deacetylase SIRT1 regulate acetylation level of APE1 and acetylation of APE1 enhances its AP-endonuclease activity both in vitro and in cells. Modulation of APE1 acetylation level in cells alters AP site repair capacity of the cell extracts in vitro. Primary tumor tissues of diverse cancer types have higher level of acetylated APE1 (AcAPE1) compared to adjacent non-tumor tissue and exhibit enhanced AP site repair capacity. Importantly, in the absence of APE1 acetylation, cells accumulate AP sites in the genome and show increased sensitivity to DNA damaging agents. Together, our study demonstrates that elevation of acetylation level of APE1 in tumor could be a novel mechanism by which cells handle the elevated levels of DNA damages in response to genotoxic stress and maintain sustained proliferation.
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.|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 & Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.|Center for Animal Sciences, School of Basic and Applied Sciences, Central University of Punjab, Bathinda 151001, Punjab, India.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Mantha
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Heyu
authors.initials: H
authors.lastname: Song
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.|Molecular Biology Research & Diagnostic Laboratory, Saroj Gupta Cancer Centre & Research Institute, Kolkata 700063, India.
authors.forename: Somsubhra
authors.initials: S
authors.lastname: Nath
authors.affiliation: Department of Pediatrics, Hematology/Oncology Division, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Sutapa
authors.initials: S
authors.lastname: Ray
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.|Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Kishor K
authors.initials: KK
authors.lastname: Bhakat
mesh_terms: D000107:Acetylation; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006801:Humans; D009243:NAD / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D009243:NAD; D056564:Sirtuin 1; D056284:Histone Deacetylase 1; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: BER; DNA damage repair; acetylation; apurinic/apyrimidinic endonuclease 1 (APE1)