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Human THO–Sin3A interaction reveals new mechanisms to prevent R-loops that cause genome instability

AuthorsSalas-Armenteros, Irene ; Pérez-Calero, Carmen; Bayona-Feliu, Aleix; Tumini, Emanuela ; Luna, Rosa ; Aguilera, Andrés
KeywordsGenome instability
Histone acetylation
Sin3A deacetylase
DNA–RNA hybrids
Issue Date2017
PublisherNature Publishing Group
CitationEMBO Journal 36(23): 3532-3547 (2017)
AbstractR-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.
Identifiersdoi: 10.15252/embj.201797208
e-issn: 1460-2075
issn: 0261-4189
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