Premium
Human THO –Sin3A interaction reveals new mechanisms to prevent R‐loops that cause genome instability
Author(s) -
SalasArmenteros Irene,
PérezCalero Carmen,
BayonaFeliu Aleix,
Tumini Emanuela,
Luna Rosa,
Aguilera Andrés
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201797208
Subject(s) - biology , genome instability , genome , genetics , human genome , instability , microbiology and biotechnology , computational biology , gene , dna , physics , dna damage , mechanics
R‐loops, formed by co‐transcriptional DNA – RNA hybrids and a displaced DNA single strand (ss DNA ), 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.