BRG1 and SMARCAL1 transcriptionally co-regulate DROSHA, DGCR8 and DICER in response to doxorubicin-induced DNA damage

Biochim Biophys Acta Gene Regul Mech. 2017 Sep;1860(9):936-951. doi: 10.1016/j.bbagrm.2017.07.003. Epub 2017 Jul 15.

Abstract

Recent investigations have emphasized the role of miRNA biogenesis proteins in the synthesis of non-coding RNA when double-strand DNA breaks are induced by ionizing radiations. However, the role of these non-coding RNA and their regulation in response to doxorubicin-induced DNA damage is not known. In this paper, BRG1 and SMARCAL1, members of the ATP-dependent chromatin remodelling family, are shown to co-regulate the transcription of DROSHA, DGCR8, and DICER in response to double-strand DNA breaks induced by doxorubicin. Both BRG1 and SMARCAL1 are needed for the upregulation of the three miRNA biogenesis genes as absence of BRG1 results in downregulation of DGCR8 and DICER while absence of SMARCAL1 results in downregulation of DROSHA. These two proteins act in coordination to upregulate expression of DROSHA, DGCR8, and DICER when cells are treated with doxorubicin. This transcriptional regulation of the miRNA biogenesis proteins is needed for the formation of 53BP1 foci as downregulation of either BRG1 or SMARCAL1 reduced the number of 53BP1 foci in DNA damaged cells. The foci formation was restored when the downregulated cells were treated with ncRNA purified from doxorubicin treated HeLa cells. From the results obtained, we conclude that the regulation of miRNA biogenesis proteins by SMARCAL1 and BRG1 is needed for the formation of non-coding RNA and thus, 53BP1 foci in response to doxorubicin-induced DNA damage.

Keywords: 53BP1; BRG1; DNA repair; Double-strand break repair; Non-coding RNA; SMARCAL1; miRNA biogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • DEAD-box RNA Helicases / genetics*
  • DNA Breaks, Double-Stranded / drug effects
  • DNA Damage / drug effects
  • DNA Damage / genetics*
  • DNA Helicases / genetics*
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Doxorubicin / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • HeLa Cells
  • Humans
  • MicroRNAs / genetics
  • Nuclear Proteins / genetics*
  • RNA, Untranslated / genetics
  • RNA-Binding Proteins / genetics*
  • Ribonuclease III / genetics*
  • Transcription Factors / genetics*
  • Transcription, Genetic / genetics*
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • DGCR8 protein, human
  • MicroRNAs
  • Nuclear Proteins
  • RNA, Untranslated
  • RNA-Binding Proteins
  • Transcription Factors
  • Doxorubicin
  • SMARCAL1 protein, human
  • DICER1 protein, human
  • DROSHA protein, human
  • Ribonuclease III
  • SMARCA4 protein, human
  • DNA Helicases
  • DEAD-box RNA Helicases