Salas-Armenteros, IrenePérez-Calero, CarmenBayona-Feliu, AleixTumini, EmanuelaLuna, RosaAguilera, Andrés2023-01-252023-01-252017-10-26http://hdl.handle.net/10668/11735R-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.enDNA–RNA hybridsSin3A deacetylaseTHO/TREXgenome instabilityhistone acetylationAcetylationCell Cycle ProteinsDNA, Single-StrandedDNA-Binding ProteinsGene Knockdown TechniquesGenomic InstabilityHEK293 CellsHeLa CellsHistonesHumansModels, BiologicalNuclear ProteinsRNARNA Processing, Post-TranscriptionalRNA-Binding ProteinsRepressor ProteinsSin3 Histone Deacetylase and Corepressor ComplexTranscription, Geneticresearch article29074626open access10.15252/embj.2017972081460-2075PMC5709763https://europepmc.org/articles/pmc5709763?pdf=renderhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709763/pdf