DHX33 Recruits Gadd45a To Cause DNA Demethylation and Regulates a Subset of Gene Transcription

Mol Cell Biol. 2020 Jun 15;40(13):e00460-19. doi: 10.1128/MCB.00460-19. Print 2020 Jun 15.

Abstract

RNA helicase DHX33 was found to regulate the transcription of multiple genes involved in cancer development. But the underlying molecular mechanism remains unclear. Here, we found DHX33 associated extensively with gene promoters at CG-rich region. Its deficiency reduced the loading of active RNA polymerase II at gene promoters. Furthermore, we observed a functional interaction between DHX33, AP-2β, and DNA demethylation protein Gadd45a (growth arrest and DNA damage inductile protein 45a) at specific gene promoters. DHX33 is required to recruit GADD45a, thereby causing local DNA demethylation through further recruiting ten-eleven-translocation (Tet) methylcytosine dioxygenase enzyme, as manifested by reduced 5-hydroxymethyl cytosine levels for a subset of genes after DHX33 deficiency. This process might involve R-loop formation in GC skew as a guidance signal at promoter sites. Our report provides for the first time, to our knowledge, original evidence that DHX33 alters epigenetic marks and regulates specific gene transcription through interaction with Gadd45a.

Keywords: Aurora kinase; CpG islands; DHX33; Gadd45a; RNA helicase; demethylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • DEAD-box RNA Helicases / metabolism*
  • DNA Demethylation*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Promoter Regions, Genetic
  • Protein Interaction Maps
  • Transcriptional Activation

Substances

  • Cell Cycle Proteins
  • GADD45A protein, human
  • DHX33 protein, human
  • DEAD-box RNA Helicases