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

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

Author information

1
Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas-Universidad Pablo de Olavide-Universidad de Sevilla, Seville, Spain.
2
Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas-Universidad Pablo de Olavide-Universidad de Sevilla, Seville, Spain rlvaro@us.es aguilo@us.es.

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

PMID:
29074626
PMCID:
PMC5709763
[Available on 2018-12-01]
DOI:
10.15252/embj.201797208
[Indexed for MEDLINE]

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