Elevated level of acetylation of APE1 in tumor cells modulates DNA damage repair

Shiladitya Sengupta, Anil K. Mantha, Heyu Song, Shrabasti Roychoudhury, Somsubhra Nath, Sutapa Ray, Kishor K. Bhakat

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)75197-75209
Number of pages13
JournalOncotarget
Volume7
Issue number46
DOIs
StatePublished - Jan 1 2016

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Keywords

  • Acetylation
  • Apurinic/apyrimidinic endonuclease 1 (APE1)
  • BER
  • DNA damage repair

ASJC Scopus subject areas

  • Oncology

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