3 years ago

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

Human THO–Sin3A interaction reveals new mechanisms to prevent R-loops that cause genome instability
Carmen Pérez-Calero, Aleix Bayona-Feliu, Irene Salas-Armenteros, Emanuela Tumini, Andrés Aguilera, Rosa Luna
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. Functional interplay of the THO mRNP biogenesis factor and the Sin3A deacetylase complex reveals a role for co-transcriptional histone deacetylation in restraining accumulation of harmful DNA–RNA hybrids.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.15252/embj.201797208

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