Role of acetylated human AP-endonuclease (APE1/Ref-1) in regulation of the parathyroid hormone gene.
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.
Bhakat
Kishor K
KK
Sealy Center for Molecular Science and Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, TX 77555-1079, USA.
Izumi
Tadahide
T
Yang
Suk-Hoon
SH
Hazra
Tapas K
TK
Mitra
Sankar
S
D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D002843:Chromatin / Q000235:genetics / Q000648:ultrastructure; D015342:DNA Probes; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives* / Q000032:analysis; D008322:Mammals; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D010280:Parathyroid Glands / Q000502:physiology*; D010281:Parathyroid Hormone / Q000235:genetics*; D010957:Plasmids; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D014162:Transfection
D002843:Chromatin; D015342:DNA Probes; D009838:Oligodeoxyribonucleotides; D010281:Parathyroid Hormone; D011994:Recombinant Proteins; D012097:Repressor Proteins; C002315:N(alpha)-acetyllysine; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D008239:Lysine