Depletion of Histone Demethylase Jarid1A Resulting in Histone Hyperacetylation and Radiation Sensitivity Does Not Affect DNA Double-Strand Break Repair

PLoS One. 2016 Jun 2;11(6):e0156599. doi: 10.1371/journal.pone.0156599. eCollection 2016.

Abstract

Histone demethylases have recently gained interest as potential targets in cancer treatment and several histone demethylases have been implicated in the DNA damage response. We investigated the effects of siRNA-mediated depletion of histone demethylase Jarid1A (KDM5A, RBP2), which demethylates transcription activating tri- and dimethylated lysine 4 at histone H3 (H3K4me3/me2), on growth characteristics and cellular response to radiation in several cancer cell lines. In unirradiated cells Jarid1A depletion lead to histone hyperacetylation while not affecting cell growth. In irradiated cells, depletion of Jarid1A significantly increased cellular radiosensitivity. Unexpectedly, the hyperacetylation phenotype did not lead to disturbed accumulation of DNA damage response and repair factors 53BP1, BRCA1, or Rad51 at damage sites, nor did it influence resolution of radiation-induced foci or rejoining of reporter constructs. We conclude that the radiation sensitivity observed following depletion of Jarid1A is not caused by a deficiency in repair of DNA double-strand breaks.

MeSH terms

  • Acetylation
  • Cell Proliferation / radiation effects
  • Chromatin / metabolism
  • DNA Breaks, Double-Stranded* / radiation effects
  • DNA Repair* / radiation effects
  • Down-Regulation / radiation effects
  • Gene Knockdown Techniques
  • Genes, Reporter
  • HeLa Cells
  • Histones / metabolism*
  • Humans
  • Lysine / metabolism
  • MCF-7 Cells
  • Plasmids / metabolism
  • Radiation Tolerance* / radiation effects
  • Radiation, Ionizing
  • Retinoblastoma-Binding Protein 2 / metabolism*

Substances

  • Chromatin
  • H2AX protein, human
  • Histones
  • KDM5A protein, human
  • Retinoblastoma-Binding Protein 2
  • Lysine

Grants and funding

This work was supported by European Commission FP7 Network of Excellence DoReMi (Low Dose research towards Multidisciplinary Integration), FP7-249689, www.doremi-noe.net, to AAF and GD; Deutsche Forschungsgemeinschaft DFG Cluster of Excellence "Munich Centre for Advanced Photonics", www.dfg.de, to AAF and GD. The funders had no role in study design, data collection, decision to publish, or preparation of the manuscript.