Role of acetylated human AP-endonuclease (APE1/Ref-1) in regulation of the parathyroid hormone gene

Kishor K. Bhakat, Tadahide Izumi, Suk Hoon Yang, Tapas Hazra, Sankar Mitra

Research output: Contribution to journalArticle

137 Citations (Scopus)

Abstract

The human AP-endonuclease (APE1/Ref-1), a multifunctional protein central to repairing abasic sites and single-strand breaks in DNA, also plays a role in transcriptional regulation. Besides activating some transcription factors, APE1 is directly involved in Ca2+-dependent downregulation of parathyroid hormone (PTH) expression by binding to negative calcium response elements (nCaREs) present in the PTH promoter. Here we show that APE1 is acetylated both in vivo and in vitro by the transcriptional co-activator p300 which is activated by Ca2+. Acetylation at Lys6 or Lys7 enhances binding of APE1 to nCaRE. APE1 stably interacts with class I histone deacetylases (HDACs) in vivo. An increase in extracellular calcium enhances the level of acetylated APE1 which acts as a repressor for the PTH promoter. Moreover, chromatin immunoprecipitation (ChIP) assay revealed that acetylation of APE1 enhanced binding of the APE1-HDACs complex to the PTH promoter. These results indicate that acetylation of APE1 plays an important role in this key repair protein's action in transcriptional regulation.

Original languageEnglish (US)
Pages (from-to)6299-6309
Number of pages11
JournalEMBO Journal
Volume22
Issue number23
DOIs
StatePublished - Dec 1 2003

Fingerprint

Parathyroid Hormone
Acetylation
Genes
Histone Deacetylases
Activating Transcription Factors
Calcium
Single-Stranded DNA Breaks
Chromatin Immunoprecipitation
Response Elements
Chromatin
Assays
Proteins
Repair
Down-Regulation
human APEX1 protein
DNA

Keywords

  • Acetylation
  • AP-endonuclease
  • Chromatin immunoprecipitation
  • Histone deacetylase
  • nCaRE
  • p300

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Role of acetylated human AP-endonuclease (APE1/Ref-1) in regulation of the parathyroid hormone gene. / Bhakat, Kishor K.; Izumi, Tadahide; Yang, Suk Hoon; Hazra, Tapas; Mitra, Sankar.

In: EMBO Journal, Vol. 22, No. 23, 01.12.2003, p. 6299-6309.

Research output: Contribution to journalArticle

Bhakat, Kishor K. ; Izumi, Tadahide ; Yang, Suk Hoon ; Hazra, Tapas ; Mitra, Sankar. / Role of acetylated human AP-endonuclease (APE1/Ref-1) in regulation of the parathyroid hormone gene. In: EMBO Journal. 2003 ; Vol. 22, No. 23. pp. 6299-6309.
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