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PMID: 14633989 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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

The EMBO journal ·Vol. 22 ·No. 23 ·2003-12-01 ·Pages 6299-309

Bhakat KK, Izumi T, Yang SH, Hazra TK, Mitra S

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.

MeSH Terms
Acetylation Animals Base Sequence Chromatin/genetics,ultrastructure DNA Probes DNA Repair DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics,metabolism Gene Deletion Gene Expression Regulation/physiology Humans Lysine/analogs & derivatives,analysis Mammals Oligodeoxyribonucleotides/chemistry Parathyroid Glands/physiology Parathyroid Hormone/genetics Plasmids Promoter Regions, Genetic Recombinant Proteins/metabolism Repressor Proteins/metabolism Transfection
Chemicals
Chromatin DNA Probes Oligodeoxyribonucleotides Parathyroid Hormone Recombinant Proteins Repressor Proteins N(alpha)-acetyllysine DNA-(Apurinic or Apyrimidinic Site) Lyase Lysine
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Bhakat Kishor K
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
Yang Suk-Hoon
Hazra Tapas K
Mitra Sankar
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/cdg595
Published
2003-12-01
Pages
6299-309
Language
English
Region
England
NLM ID
8208664
PMCID
PMC291836
Subset
IM
Grants
NCI NIH HHS · R01 CA53791 · United States
NIEHS NIH HHS · R01 ES008457 · United States
NCI NIH HHS · R01 CA053791 · United States
NIA NIH HHS · P01 AG10514 · United States
NIEHS NIH HHS · R01 ES08457 · United States
NIEHS NIH HHS · P30 ES006676 · United States
NIEHS NIH HHS · ES06676 · United States
External Links
PubMed source DOI: 10.1093/emboj/cdg595 PMC Full Text View journal details
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