Poly(ADP-ribose) polymerase-1 down-regulates BRCA2 expression through the BRCA2 promoter

Jinhua Wang, Chunjing Bian, Jing Li, Fergus J Couch, Kangjian Wu, Robert Chunhua Zhao

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Expression of the BRCA2 tumor suppressor gene is tightly linked to its roles in DNA damage repair and maintenance of chromosomal stability and genomic integrity. Three transcription factors that activate (USF, NF-κB, and Elf1) and a single factor that represses (SLUG) BRCA2 promoter activity have been reported. In addition, a 67-bp region (-582 to -516) associated with inhibition of promoter activity has been identified. However, it remains unclear how the 67-bp region contributes to regulation of BRCA2 expression. Here, we describe the affinity purification of a 120-kDa protein that binds to a silencer-binding region within the 67-bp repression region of the BRCA2 promoter. Mass spectrometry revealed the identity of the protein as poly-(ADP-ribose) polymerase-1 (Parp-1). Gel shift, antibody super-shift, and chromatin immunoprecipitation (ChIP) assays demonstrated that Parp-1 is associated with the BRCA2 promoter both in vitro and in vivo. Furthermore, Parp-1 inhibitors (either 3-AB or NU1025) and Parp-1 gene specific siRNA resulted in increased levels of endogenous BRCA2 expression. Inhibition of Parp-1 activity (by 3-AB) reduced histone 3 lysine 9 acetylation and blocked Parp-1 binding to the BRCA2 promoter. These results indicate that Parp-1 down-regulates BRCA2 expression through an interaction with a repression region of the BRCA2 promoter.

Original languageEnglish (US)
Pages (from-to)36249-36256
Number of pages8
JournalJournal of Biological Chemistry
Volume283
Issue number52
DOIs
StatePublished - Dec 26 2008

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Poly(ADP-ribose) Polymerases
Down-Regulation
Genetic Promoter Regions
Upstream Stimulatory Factors
Genes
Acetylation
Chromosomal Instability
Chromatin Immunoprecipitation
Poly (ADP-Ribose) Polymerase-1
Tumor Suppressor Genes
DNA Repair
Histones
Small Interfering RNA
Lysine
DNA Damage
Chromatin
Purification
Mass spectrometry
Tumors
Assays

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Poly(ADP-ribose) polymerase-1 down-regulates BRCA2 expression through the BRCA2 promoter. / Wang, Jinhua; Bian, Chunjing; Li, Jing; Couch, Fergus J; Wu, Kangjian; Zhao, Robert Chunhua.

In: Journal of Biological Chemistry, Vol. 283, No. 52, 26.12.2008, p. 36249-36256.

Research output: Contribution to journalArticle

Wang, Jinhua ; Bian, Chunjing ; Li, Jing ; Couch, Fergus J ; Wu, Kangjian ; Zhao, Robert Chunhua. / Poly(ADP-ribose) polymerase-1 down-regulates BRCA2 expression through the BRCA2 promoter. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 52. pp. 36249-36256.
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