Human THO-Sin3A Interaction Reveals New Mechanisms to Prevent R-loops That Cause Genome Instability

EMBO J. 2017 Dec 1;36(23):3532-3547. doi: 10.15252/embj.201797208. Epub 2017 Oct 26.

Abstract

R-loops, formed by co-transcriptional DNA-RNA hybrids and a displaced DNA single strand (ssDNA), fulfill certain positive regulatory roles but are also a source of genomic instability. One key cellular mechanism to prevent R-loop accumulation centers on the conserved THO/TREX complex, an RNA-binding factor involved in transcription elongation and RNA export that contributes to messenger ribonucleoprotein (mRNP) assembly, but whose precise function is still unclear. To understand how THO restrains harmful R-loops, we searched for new THO-interacting factors. We found that human THO interacts with the Sin3A histone deacetylase complex to suppress co-transcriptional R-loops, DNA damage, and replication impairment. Functional analyses show that histone hypo-acetylation prevents accumulation of harmful R-loops and RNA-mediated genomic instability. Diminished histone deacetylase activity in THO- and Sin3A-depleted cell lines correlates with increased R-loop formation, genomic instability, and replication fork stalling. Our study thus uncovers physical and functional crosstalk between RNA-binding factors and chromatin modifiers with a major role in preventing R-loop formation and RNA-mediated genome instability.

Keywords: DNA–RNA hybrids; Sin3A deacetylase; THO/TREX; genome instability; histone acetylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Cell Cycle Proteins / metabolism*
  • DNA, Single-Stranded / chemistry
  • DNA, Single-Stranded / genetics
  • DNA, Single-Stranded / metabolism
  • Gene Knockdown Techniques
  • Genomic Instability*
  • HEK293 Cells
  • HeLa Cells
  • Histones / metabolism
  • Humans
  • Models, Biological
  • Nuclear Proteins / metabolism*
  • RNA / chemistry
  • RNA / genetics
  • RNA / metabolism
  • RNA Processing, Post-Transcriptional
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Transcription, Genetic

Substances

  • Cell Cycle Proteins
  • DNA, Single-Stranded
  • Histones
  • Nuclear Proteins
  • Repressor Proteins
  • SIN3A transcription factor
  • THOC1 protein, human
  • RNA