title: The oxidative demethylase ALKBH3 marks hyperactive gene promoters in human cancer cells.
abstract: BACKGROUND
  The oxidative DNA demethylase ALKBH3 targets single-stranded DNA (ssDNA) in order to perform DNA alkylation damage repair. ALKBH3 becomes upregulated during tumorigenesis and is necessary for proliferation. However, the underlying molecular mechanism remains to be understood.
  
  
  METHODS
  To further elucidate the function of ALKBH3 in cancer, we performed ChIP-seq to investigate the genomic binding pattern of endogenous ALKBH3 in PC3 prostate cancer cells coupled with microarray experiments to examine the expression effects of ALKBH3 depletion.
  
  
  RESULTS
  We demonstrate that ALKBH3 binds to transcription associated locations, such as places of promoter-proximal paused RNA polymerase II and enhancers. Strikingly, ALKBH3 strongly binds to the transcription initiation sites of a small number of highly active gene promoters. These promoters are characterized by high levels of transcriptional regulators, including transcription factors, the Mediator complex, cohesin, histone modifiers, and active histone marks. Gene expression analysis showed that ALKBH3 does not directly influence the transcription of its target genes, but its depletion induces an upregulation of ALKBH3 non-bound inflammatory genes.
  
  
  CONCLUSIONS
  The genomic binding pattern of ALKBH3 revealed a putative novel hyperactive promoter type. Further, we propose that ALKBH3 is an intrinsic DNA repair protein that suppresses transcription associated DNA damage at highly expressed genes and thereby plays a role to maintain genomic integrity in ALKBH3-overexpressing cancer cells. These results raise the possibility that ALKBH3 may be a potential target for inhibiting cancer progression.
authors.affiliation: Division of Newborn Medicine and Program in Epigenetics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115 USA ; Department of Cell Biology, Harvard Medical School, Boston, MA 02115 USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Liefke
authors.affiliation: University Medical Center, Department of General-, and Visceral Surgery, D-37075 Göttingen, Germany.
authors.forename: Indra M
authors.initials: IM
authors.lastname: Windhof-Jaidhauser
authors.affiliation: University Medical Center, Department of General-, and Visceral Surgery, D-37075 Göttingen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Gaedcke
authors.affiliation: University Medical Center, Transcription Analysis Laboratory, D-37073 Göttingen, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Salinas-Riester
authors.affiliation: Epigenetics Laboratory, Institute of Biomedical Sciences, Fudan University, Shanghai, 200032 China.
authors.forename: Feizhen
authors.initials: F
authors.lastname: Wu
authors.affiliation: University Medical Center, Department of General-, and Visceral Surgery, D-37075 Göttingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Ghadimi
authors.affiliation: University Medical Center, Department of General-, and Visceral Surgery, D-37075 Göttingen, Germany ; Division of Newborn Medicine and Program in Epigenetics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115 USA ; Department of Cell Biology, Harvard Medical School, Boston, MA 02115 USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Dango