THOC5 complexes with DDX5, DDX17, and CDK12 to regulate R loop structures and transcription elongation rate

THOC5, a member of the THO complex, is essential for the 3'processing of some inducible genes, the export of a subset of mRNAs and stem cell survival. Here we show that THOC5 depletion results in altered 3'cleavage of >50% of mRNAs and changes in RNA polymerase II binding across genes. THOC5 is recruited close to high-density polymerase II sites, suggesting that THOC5 is involved in transcrip-tional elongation. Indeed, measurement of elongation rates in vivo demonstrated decreased rates in THOC5-depleted cells. Furthermore, THOC5 is preferentially recruited to its target genes in slow polymerase II cells compared with fast poly-merase II cells. Importantly chromatin-associated THOC5 interacts with CDK12 (a modulator of transcription elongation) and RNA helicases DDX5, DDX17, and THOC6 only in slow polymerase II cells. The CDK12/THOC5 interaction promotes CDK12 recruitment to R-loops in a THOC6-dependent manner. These data demonstrate a novel function of THOC5 in transcription elongation.

Automated summary

THOC5 is essential for the 3'processing of inducible genes, mRNA export, and stem cell survival. Depletion of THOC5 leads to altered mRNA 3'cleavage and changes in RNA polymerase II binding across genes. THOC5 is recruited near high-density polymerase II sites, suggesting its involvement in transcriptional elongation.